tbuckley/cabot-search huggingface dataset:
Abstract LB-275: Single cell analysis identified LY6D as a novel marker of castration-resistant multipotent luminal progenitors
Authors: Douglas E. Linn, João Barros-Silva, Guoji Guo, Michael Brown, Garry Ashton, Noel W. Clarke, Guo-Cheng Yuan, Stuart H. Orkin, Esther Baena, Zhe Li
Journal: Cancer Research (2016)

Abstract The cellular origin of castration-resistant prostate cancer (CRPC) remains largely unsolved. We compared single-cell expression profiles of prostate cells sorted from hormone-naïve and castrated mice. Our single-cell analysis reveals that the prostate luminal lineage is highly heterogeneous. A subset of prostate cells in the luminal lineage characterized by high expression levels of luminal lineage markers including cytokeratin 8 (Krt8) and androgen receptor (Ar) genes, as well as prostate stem/progenitor marker genes (e.g., Trop2/Tacstd2, Sca1/Ly6a), and intermediate levels of basal genes (e.g. Trp63, Krt5), is enriched upon castration. We validated LY6D as a novel marker of castration-resistant (CR) multipotent luminal progenitor. Organoid culture revealed that LY6D+ prostate cells, including LY6D+ prostate luminal cells, were enriched with multipotent organoid-forming cells under androgen-deprivation. Lineage-tracing using Krt8-CreER mice revealed that in wild-type mice, LY6D+ CR luminal cells appeared to produce LY6D- luminal cells upon regeneration; however, when under the Pten-loss background, LY6D+ Pten-null luminal cells gave rise to LY6D+ luminal cancer cells. Furthermore, upon induced loss of Pten, prostate cancers originating from Krt8+ CR luminal cells were LY6D+ high-grade and were more advanced than those originating from hormone-naïve luminal cells. Lastly, in prostate cancer patients, LY6D amplification/upregulation correlates with advanced disease. Overall, our results uncover the luminal lineage heterogeneity and identify LY6D as a novel tumor-initiating cell marker of CRPC. Citation Format: Douglas E. Linn, João Barros-Silva, Guoji Guo, Michael Brown, Garry Ashton, Noel W. Clarke, Guo-Cheng Yuan, Stuart H. Orkin, Esther Baena, Zhe Li. Single cell analysis identified LY6D as a novel marker of castration-resistant multipotent luminal progenitors. [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 LB-275.
Prevalence of written advance directives (AD) among cancer care providers at a community-based cancer center
Authors: B. A. Hammes, J. A. Lee, M. A. Mathiason, M. T. Ertz, L. L. Sheldon, R. S. Go
Journal: Journal of Clinical Oncology (2006)

18563 Background: Cancer care providers frequently discuss AD with their patients. The providers’ own attitudes toward end-of-life planning likely influence the choices and actions of their patients. We investigated the prevalence of written AD among the care providers at our community-based cancer center. Methods: All cancer center employees who have face-to-face contacts with patients (N=170) were sent an email survey in October 2005. This included medical (physicians, 15), associate (physician assistants and nurse practitioners, 7), and support (nurses, radiation therapists, medical or nurse assistants, and patient liaisons; 148) staffs. We collected data on demographics, work history, and AD. Results: A reply was obtained from 136 (80%) individuals. There were more females (90.2%) and the median age was 43 years (range, 20–63). While 82.8% reported to have discussed their wishes regarding future life-sustaining medical care with those closest to them, only 35.1% had a written AD: medical (58.3%), associate (50%), and support staffs (32.2%). Among those with AD, only 66% had made their own care providers aware of this. The top 5 factors that influenced providers whether to have or not to have AD were: experience at work (36.6%), spouse/domestic partner (25.4%), time to complete written AD (23.9%), family members/friends (21.6%) and children (19.4%). Interestingly, no one considered medical condition or illness as a factor. Increased age was significantly associated with having AD (odds ratio: 1.068; 95% CI:1.029–1.108), while the sex, number of years working with cancer patients, provider role, and marital/living status were not. Among the medical and associate staffs, 55.6% reported routinely discussing AD with their patients. Although all medical/associate staffs rated themselves as knowledgeable about and comfortable with discussing AD, the group who had AD was more apt to rate themselves as very knowledgeable and very comfortable. Conclusions: Only about a third of all cancer care providers and about half of cancer physicians at our institution have a written AD. Despite work experience with a patient population having a high mortality rate, cancer care providers do not adequately communicate end-of-life planning to their own health care providers. No significant financial relationships to disclose.
A phase I extension study of BBI608, a first-in-class cancer stem cell (CSC) inhibitor, in patients with advanced solid tumors.
Authors: Derek J. Jonker, Joe Stephenson, William Jeffery Edenfield, Jeffrey G. Supko, Youzhi Li, Wei Li, Matthew Hitron, David Leggett, David Kerstein, Chiang Li
Journal: Journal of Clinical Oncology (2014)

2546 Background: BBI608, an orally-administered first-in-class cancer stemness inhibitor, blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibiting Stat3, β-catenin, and Nanog pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. In a phase 1 study, BBI608 demonstrated tolerability as well as signs of anti-cancer activity in patients with solid tumors. This phase 1 extension study evaluated a formulation designed for pivotal trials to determine pharmacokinetics (PK) in patients with advanced cancer. Methods: Day 1, patients received a single 500mg dose of the original BBI608 formulation (DP1). Day 4 and 8, a higher strength capsule designed for pivotal trials (DP2A) was given with fasting then fed conditions. DP2A was then administered daily until disease progression or unacceptable toxicity. Endpoints were safety, PK and preliminary anticancer activity. Results: DP2A was evaluated in 24 patients. No significant difference in plasma exposure between DP1 and DP2A, and no significant food effect were observed. Nine patients received BBI608 DP2A 4 h apart (DP2A-4h) only, and 15 patients received BBI608 DP2A 500 mg bid 12 h apart (DP2A-12h). Despite PK equivalence to DP1, DP2A-4 h was associated with higher frequency of gastrointestinal (GI) adverse events (AE) than observed in the prior study, including diarrhea, abdominal cramps, nausea/vomiting, anorexia, and fatigue. In contrast, DP2A-12 h had fewer GI AE and was selected for the extension study. Among 15 patients receiving DP2A-12h, prolonged stable disease was observed in 2 of 7 non-CRC patients (ovarian cancer-16 wk and anal squamous cancer-32 wk) and among 8 CRC patients enrolled, disease control was observed in 67% evaluable for response (4/6), with progression free survival and overall survival at 17 weeks and 39 weeks, respectively. Conclusions: The recommended dosing regimen for BBI608 in pivotal trials was determined to be about 500 mg bid q12 h. Signs of anticancer activity were observed in patients with CRC, anal squamous carcinoma, and ovarian cancer. Clinical trial information: NCT01775423.
Abstract 2105: c-Met hyperactivation is an universal resistance mechanism to both first and third generation EGFR inhibitors
Authors: Puyu Shi, You-Take Oh, Guojing Zhang, Weilong Yao, Ping Yue, Rajani Kanteti, Jacob Riehm, Ravi Salgia, Taofeek Owonikoko, Suresh S. Ramalingam, Mingwei Chen, Shi-Yong Sun
Journal: Cancer Research (2016)

Abstract c-Met amplification and acquisition of a second T790M mutation are key mechanisms accounting for majority of resistant cases to first generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs; i.e., erlotinib). The third generation EGFR-TKIs (e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants while sparing wild-type EGFR, represent very promising therapeutic options for NSCLC patients who have become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. We show that c-Met amplification and hyperactivation is an universal mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed elevated levels of c-Met (due to gene amplification) and p-c-Met and were cross-resistant to AZD9291 or erlotinib. Both chemical and genetic inhibition of c-Met overcame the resistance of these cell lines to AZD9291 including enhancement of apoptosis or G1 cell cycle arrest. Consistently the combination of AZD9291 and c-Met inhibition effectively inhibited the growth of both erlotinib- and AZD9291-resistant HCC827 xenografts in nude mice. Hence, we suggest that inhibition of c-Met is also an effective strategy to overcome resistance of EGFR-mutated NSCLCs with c-Met amplification or hyperactivation to AZD9291, providing the rationale for clinical development of this novel combination strategy. (SSR, TKO and SYS are Georgia Research Alliance Distinguished Cancer Scientists) Citation Format: Puyu Shi, You-Take Oh, Guojing Zhang, Weilong Yao, Ping Yue, Rajani Kanteti, Jacob Riehm, Ravi Salgia, Taofeek Owonikoko, Suresh S. Ramalingam, Mingwei Chen, Shi-Yong Sun. c-Met hyperactivation is an universal resistance mechanism to both first and third generation EGFR inhibitors. [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 2105.
Abstract 4013: Transcriptionally mediated effects of radiation on the expression of immune susceptibility markers in murine and human melanoma
Authors: Lauryn R. Werner, Monica Gressett, Maureen Riegert, Shyhmin Huang, Joseph G. Kern, Amy Erbe, Paul M. Harari, Paul M. Sondel, Zachary S. Morris
Journal: Cancer Research (2016)

Abstract Radiation therapy (RT) may enhance tumor susceptibility to immune response. We and others have observed a cooperative interaction between RT and various immunotherapies, which appears dependent on the relative sequencing of each therapy. We reported a synergistic interaction between RT and the antibody-dependent cell-mediated cytotoxicity (ADCC) response to tumor-specific monoclonal antibodies (mAb) in murine melanoma. We reported enhanced cooperative effect when immunotherapy is administered 6-10 days after RT compared to administration on days 1-5 or 11-15. We hypothesized that this might reflect a delayed, transcriptionally-mediated effect of RT on the expression of tumor markers of immune susceptibility. In this study, we investigated the effect of RT on a variety of immune susceptibility markers at both transcriptional and post-translational levels to explore mechanisms behind the observed RT-induced changes. We used flow cytometry to examine the time course of phenotypic changes in immune susceptibility markers in B78 murine melanoma cells following in vitro RT. We observed a time- and RT dose-dependent increase in the expression of specific death receptors (Fas, DR5), as well as T cell co-stimulatory/co-repressor ligands (PD-L1, CD80). The timing of these changes correlated with tumor susceptibility to ADCC immune response in vivo. All protein expression changes observed by flow cytometry were found to occur over a similar time course by quantitative polymerase chain reaction (qPCR), suggesting that RT-induced protein expression changes were mediated by changes in transcriptional activity. Using high throughput qPCR, we observed a similar time course of transcriptional effects in additional markers of tumor cell immune susceptibility, including Fas, MHC I, CD40, and others. We compared the effect of RT on these markers in human and mouse melanoma cell lines and observed a comparable time course for transcript-level changes across species. This study sheds light on the mechanistic basis of time sensitivity in the interaction of RT with ADCC in vivo and suggests opportunities to enhance anti-tumor immune response by combining RT and immunotherapeutic agents. Such findings bear relevance for research investigating the potential role for RT in driving and optimizing the response to various cancer immunotherapies. Citation Format: Lauryn R. Werner, Monica Gressett, Maureen Riegert, Shyhmin Huang, Joseph G. Kern, Amy Erbe, Paul M. Harari, Paul M. Sondel, Zachary S. Morris. Transcriptionally mediated effects of radiation on the expression of immune susceptibility markers in murine and human melanoma. [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 4013.
Abstract 2172: Circle Akt in: Epitope catalyzed assembly of macrocyclic therapeutics against phosphorylated Akt
Authors: Arundhati Nag
Journal: Cancer Research (2016)

Abstract An approach to drugging ‘undruggable’ target proteins using macrocyclic, epitope targeted peptide based affinity reagents is demonstrated. An unbiased comprehensive Cu-catalyzed Azide Alkyne Cycloaddition cyclized peptide macrocyclic library is synthesized and screened against the phoshoS474 containing Hydrophobic Motif (HM) peptide epitope of Akt2. The best macrocyclic ligand, which exhibits specificity at the peptide and protein levels, is further extended through an in situ click screen to yield bivalent macrocyclic reagent with high affinity and specificity. The bivalent peptide, targeted against the phospho-S474 region of Akt, inhibits the Akt kinase in in vitro kinase assays. This ligand is being optimized, through systematic changes in its composition, to increase its cell permeability characteristics, so that its effects can be studied in Akt overexpressing carcinoma cell lines. The optimized macrocyclic peptide can eventually be used as an in vivo imaging probe and as a peptide inhibitor drug. Citation Format: Arundhati Nag. Circle Akt in: Epitope catalyzed assembly of macrocyclic therapeutics against phosphorylated Akt. [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 2172.
Abstract 206: Cytochrome c oxidase subunit 5a (COX5A) is identified as a potential therapeutic target for lung cancer with high therapeutic index through a pooled shRNA screen
Authors: Toshio Kato, Mitsuo Sato, Masashi Kondo, Tomohiko Kakumu, Naoyuki Yogo, Tetsunari Hase, Masahiro Morise, Yoshionori Hasegawa, John D. Minnna, Luc Girard
Journal: Cancer Research (2016)

Abstract [Background]Recent advances in high throughput analysis of genetic and epigenetic alterations revealed numerous changes in lung cancer cells. It is vital to sort out genes that substantially contribute to oncogenic properties of cancer cells from these numerous altered genes by performing a functional screening because such genes could serve as valuable therapeutic targets. To this end, we performed a screening with a pooled shRNA library for genes critical for survival and/or proliferation in lung cancer cells. [Methods and Results]A pooled shRNA library comprising 5,000 genes, with 3 to 7 constructs per gene, were transduced in NCI-H460 lung cancer cell line. Subsequently, genomic DNA was extracted from the transduced cells and numbers of shRNA for each gene were quantified by next generation sequencing. Through a stringent filtering process we narrowed down genes to a list of 24 candidates as potentially target genes. Next, we integrated data of genome-wild gene expression and copy number analyses of a panel of lung cancer cell lines to narrow down to genes more relevant to lung cancer. Through these processes, we listed up several candidate genes. Among them, we focused on Cytochrome c oxidase subunit 5a (COX5A), one of the nuclear encoded subunits of cytochrome c oxidase, the terminal protein of the mitochondrial electron transport chain. Importantly, COX5A knockdown didn't suppress growth of HBEC3, a normal control cell line, suggesting that therapeutics of targeting COX5A may have high therapeutic index. [Conclusions]Our results suggest that inhibiting COX5A may be an attractive strategy for the treatment of NSCLC with high therapeutic index. Citation Format: Toshio Kato, Mitsuo Sato, Masashi Kondo, Tomohiko Kakumu, Naoyuki Yogo, Tetsunari Hase, Masahiro Morise, Yoshionori Hasegawa, John D. Minnna, Luc Girard. Cytochrome c oxidase subunit 5a (COX5A) is identified as a potential therapeutic target for lung cancer with high therapeutic index through a pooled shRNA screen. [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 206.
Abstract 2907: Eugenol potentiates the effect of cisplatin on cancer stem-like cells through targeting the NF-κB pathway
Authors: Syed S. Islam, Al-Sharif Ibtehaj, Sultan Ahlam, Abdelilah Aboussekhra
Journal: Cancer Research (2016)

Abstract Triple-negative subtype of breast cancer (TNBC) contains exclusively tumorigenic and often endowed with self-renewing and resistance to cytotoxic chemotherapy, such as, paclitaxel resulting in relative increases in CSCs phenotype. Signaling through NF-kB may be essential for the CSCs self-renewal and could present potential target for novel treatment in breast cancer patients. We explored the possible involvement of NF-kB pathway that contribute to the functions and maintenance of breast CSCs and targeting this pathway by cisplatin combining with a natural product eugenol both in vitro and in vivo, using estrogen dependent (MCF-7) and independent (MDA-MB-231, MDA-MB-468 and BT-20) cell lines and xenografted both subcutaneous and orthotopic (fat pad) sites in nude mice. Chromatin immunoprecipitation (ChIP) assay was utilized to assess the NF-kB associated DNA binding capacity in promoter region. Surprisingly, neither cisplatin nor eugenol was capable of complete diminishing the CSCs populations. Cisplatin alone administration partially diminished apoptosis, mammospheres formation, aldehyde dehydrogenase 1 (ALDH1) activity, invasion and growth on nude mice. We observed cisplatin-induced activation of NF-kB associated with survival and regrowth of mamospheres. For effective elimination of CSCs phenotype by cisplatin, we cotreated cells with eugenol. Combination of eugenol and cisplatin significantly eradicated cisplatin induced NF-kB DNA binding capability assed by EMSA and ChIP assays, which was associated with abrogated apoptosis, mammospheres formation, ALDH1 activity and invasion. In vivo, combination therapy reduced the tumor size in synergistic manner. This was possibly due to induction of apoptosis, inhibition of proliferation, angiogenesis and downregulation of cisplatin-induced expression of proteins of NF-kB target genes. Although treatment of mammospheres by cisplatin partially induced the CSCs population through interleukin (IL)-6 pathway, however, only coadministration of eugenol and cisplatin reduced the numbers of CSCs to virtually undeletable levels in vitro and in vivo. Our data suggest that eugenol may be well suited to increase targeting of breast CSCs by cisplatin. Citation Format: Syed S. Islam, Al-Sharif Ibtehaj, Sultan Ahlam, Abdelilah Aboussekhra. Eugenol potentiates the effect of cisplatin on cancer stem-like cells through targeting the NF-κB pathway. [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 2907.
Abstract 3646: Highly sensitive and cost-effective detection of somatic cancer variants using single-molecule, real-time sequencing
Authors: Steve Kujawa, Anand Sethuraman, Kevin Eng, Primo Baybayan, Lien Heyrman, Jurgen Del Favero
Journal: Cancer Research (2016)

Abstract Next-Generation Sequencing (NGS) technologies allow for molecular profiling of cancer samples with high sensitivity and speed at reduced cost. For efficient profiling of cancer samples, it is important that the NGS methods used are not only robust but also capable of accurately detecting low-frequency somatic mutations. Single Molecule, Real-Time (SMRT®) Sequencing offers several advantages, including the ability to sequence single molecules with very high accuracy (&amp;gt;QV40) using the circular consensus sequencing (CCS) approach. The availability of genetically defined, human genomic reference standards provides an industry standard for the development and quality control of molecular assays for studying cancer variants. Here we characterize SMRT Sequencing for the detection of low-frequency somatic variants using the Quantitative Multiplex DNA Reference Standards from Horizon Diagnostics, combined with amplification of the variants using the Multiplicom Tumor Hotspot MASTR Plus assay. First, we sequenced a reference standard containing precise allelic frequencies from 1% to 24.5% for major oncology targets verified using digital PCR. This reference material recapitulates the complexity of tumor composition and serves as a well-characterized control. The control sample was amplified using the Multiplicom Tumor Hotspot MASTR Plus assay that targets 252 amplicons (121-254 bp) from 26 relevant cancer genes, which includes all 11 variants in the control sample. We also sequenced a second sample containing a series of mixes, each with known mutations, at levels below 10% and down to 0.01%. PCR-amplified targets were sequenced and analyzed using SMRT Sequencing to identify the variants and determine the observed frequency. The random error profile and high-accuracy CCS reads make it possible to accurately detect low-frequency somatic variants. Citation Format: Steve Kujawa, Anand Sethuraman, Kevin Eng, Primo Baybayan, Lien Heyrman, Jurgen Del Favero. Highly sensitive and cost-effective detection of somatic cancer variants using single-molecule, real-time sequencing. [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 3646.