bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-256: Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor
Authors: Byun Jooyun , Song Taehun , Kim Donghyun , Son Junhyeng , Lee Kwang-Ok , Lee Jaeho , Kim Yong Hoon , Lee Young-Mi , Suh Kwee Hyun
Published: August 2015

The first-generation of EGFR1 inhibitors (Gefitinib and Erlotinib) has significant clinical benefits in NSCLC caused by activating mutations, but the efficacy of these agents is often limited due to the emergence of drug resistance conferred by a gatekeeper residue, T790M. HM61713 is a third-generation EGFR tyrosine kinase inhibitor that has been evaluated as a novel therapeutic agent for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations.

HM61713 is an orally active and a novel EGFR mutant selective inhibitor which is potent on resistance mutation (T790M) without affecting EGFR wild type at efficacious dose level. HM61713 showed an anti-cancer activity in several EGFR mutant lung cancer cell lines including T790M mutation harboring cell line.

Integrated pharmacokinetic - pharmacodynamic - xenograft tumor model (PK-PD-XTG) was used to characterize the relationship between HM61713 plasma concentration and tumor growth inhibition (TGI) in H1975 (T790M mutation) xenograft model. Simple one-compartment model applied re-absorption compartment with first-order absorption/elimination was used to describe HM61713 plasma concentration-time profiles. Biophase distribution model with baseline inhibition Emax equation was applied to characterize the PD marker (p-EGFR) and tumor volume shrinkage was explained by michaelis-menten kinetics of p-EGFR. Estimated in vivo IC50 value of p-EGFR inhibition (%) based on plasma free concentration in xenograft mice was 1.14 ng/mL. The human PD marker response curve and the tumor growth inhibition plot were obtained by replacing the mice PK to human PK in our developed model based on the hypothesis thattranslation providesa good relationship of surrogate mice tumor PD to human tumor regression corresponding human PK. According to our simulated curves, we predicted appropriate human active dose from 300 to 800 mg/man and it would be an efficacious dose in patients with NSCLC harboring the EGFR activating and also with T790M resistant mutation. Currently, HM61713 is undergoing in clinical trial phase I/II in NSCLC (ClinicalTrials.gov, NCT01588145).

Citation Format: Jooyun Byun, Taehun Song, Donghyun Kim, Junhyeng Son, Kwang-Ok Lee, Jaeho Lee, Yong Hoon Kim, Young-Mi Lee, Kwee Hyun Suh. Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2015-LB-256
Abstract LB-269: Nutritional effect on CD44 in head and neck cancer
Authors: Almuhaimid Turki M. , Alotaibi Faisal F. , Rearegue Erika , Goodwin William , Franzmann Elizabeth
Published: August 2015

Head and neck (HN) cancer incidence accounts for more than 550,000 cases annually worldwide, with an estimated of 55,000 Americans developing head and neck cancer each year. There are multiple risk factors associated with HN cancer including smoking, alcohol consumption, human papillomavirus (HPV) infection, genetic predisposition, poor oral hygiene, periodontal disease and poor diet. According to World Health Organization (WHO), 35 - 55% of human cancers and approximately 15% of oropharyngeal cancers can be attributed to dietary deficiencies or imbalances. There is convincing evidence that we can reduce the risk of cancer, including that of oral cancer through improved nutrition. CD44 is a cancer stem cell marker associated with HN cancer and poor prognosis. Protein levels in saliva are also associated with HN cancer risk. This study will investigate the relationship between nutritional effect of a balanced diet which includes fruits and vegetables and levels of CD44 and salivary protein. 150 participants diagnosed with HN cancer and 150 controls were frequency matched for tobacco use, alcohol, age, gender, race and socioeconomic status. Participants completed a lifestyle questionnaire which included questions about fruit and vegetable consumption. Oral rinse CD44 and protein levels were measured in both groups. We did a preliminary investigation on the number of servings of juice, salad, fruits, carrots, potato and other vegetables within the cancer case and control groups to determine whether there was an association between these dietary variables and CD44 and protein levels. HN cancer cases who ate salad one or more times per week were found to have significantly lower CD44 levels than those who ate salad less frequently (4.22ng/ml verses 7.09 ng/ml p = 0. 004). Since high CD44 levels are associated with worse prognosis, these findings suggest that dietary factors such as greater salad intake may be associated with better HN cancer prognosis.

Citation Format: Turki M. Almuhaimid, Faisal F. Alotaibi, Erika Rearegue, William Goodwin, Elizabeth Franzmann. Nutritional effect on CD44 in head and neck cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-269. doi:10.1158/1538-7445.AM2015-LB-269
Abstract LB-273: Molecular targeting Neu1 with oseltamivir phosphate abrogates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast cancer
Authors: Szewczuk Myron R. , Haxho Fiona , Allison Stephanie , Alghamdi Farah , Brodhagen Lacey , Kuta Victoria , Abdulkhalek Samar , Neufeld Ronald
Published: August 2015

Patients with triple-negative breast cancers (TNBCs) lacking the estrogen, progesterone, and epidermal growth factor (EGF) receptor-2 (HER2/neu) receptors have typical high grading, frequent relapses, and exhibit poorer outcomes or prognosis compared with the other subtypes. No current targeted therapies are effective for TNBC. Here, preclinical studies on the antitumor activity of oseltamivir phosphate (OP) monotherapy was investigated to identify its role in tumor neovascularization, growth, invasiveness, and long-term survival in RAGxCγ double mutant mouse model of human TNBC. Sialidase, WST-1, and immunohistochemistry assays were used to evaluate sialidase activity, cell viability, and expression levels of E-, and N-cadherins, and host CD31+/PECAM-1 cells in paraffin-embedded TNBC MDA-MB-231 tumors grown in these mice. OP, anti-Neu1, and matrix metalloproteinase-9-specific inhibitor blocked Neu1 activity associated with EGF-stimulated MDA-MB-231 cells. OP treatment of MDA-MB-231 and MCF-7 cells and their stable tamoxifen-resistant clones reproducibly and dose-dependently reduced the sialidase activity associated with EGF-stimulated live cells and the cell viability after 72 hours of incubation. Combination of 1 μM cisplatin, 5-fluorouracil, paclitaxel, gemcitabine, or tamoxifen with OP in a dose-dependent manner significantly reduced cell viability at 24, 48, and 72 hrs when compared to the chemotherapeutic alone. Heterotopic xenografts of MDA-MB-231 tumors developed bloody tumor vascularization in these mice. OP treatment at 30 mg/kg daily I.P. treatment reduced tumor vascularization and growth rate with significant reduction in tumor weight and spread to the lungs compared with the untreated cohorts. OP treatment at 50 mg/kg completely ablated tumor vascularization, growth and spread to the lungs, with significant long-term survival for 180 days post-implantation, tumor shrinking, and no relapses after 56 days off-drug. OP 30 mg/kg cohort tumors had significantly reduced levels of human N-cadherins and host CD31+ endothelial cells with concomitant significant expression of E-cadherins compared to the untreated cohorts. These findings signify a novel treatment therapy for TNBC.

Citation Format: Myron R. Szewczuk, Fiona Haxho, Stephanie Allison, Farah Alghamdi, Lacey Brodhagen, Victoria Kuta, Samar Abdulkhalek, Ronald Neufeld. Molecular targeting Neu1 with oseltamivir phosphate abrogates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-273. doi:10.1158/1538-7445.AM2015-LB-273
Abstract LB-274: Transcriptional factor Snail and MMP-9 signaling axis amplifies Neu1-MMP-9 crosstalk on EGF receptor to regulate tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
Authors: Szewczuk Myron R. , Abdulkhalek Samar , Geen Olivia , Brodhagen Lacey , Haxho Fiona , Alghamdi Farah , Allison Stephanie , Simmons Duncan , O'Shea Leah , Neufeld Ronald
Published: August 2015

Snail is a transcriptional factor and repressor of E-cadherin. It is well known for its role in cellular invasion, epithelial to mesenchymal transition (EMT), tumor progression and metastases. shRNA lentiviral knockdown (KD) of Snail and its associated member Slug in human A2780 ovarian epithelial carcinoma cell line was investigated to identify its role in tumor neovascularization. Live cell sialidase, WST-1 and immunohistochemistry assays were used to evaluate sialidase activity, cell proliferation and the expression levels of tumor E-, N- and VE-cadherins, and host endothelial CD31+(PECAM-1) cells in A2780, A2780 Snail KD and A2780 Slug KD tumors grown in RAGxCγ double mutant mice. Oseltamivir phosphate (OP), anti-Neu1and MMP-9 specific inhibitor blocked Neu1 activity associated with epidermal growth factor (EGF) stimulated A2780 cells. Silencing Snail and Slug in A2780 cells abrogated the Neu1 activity following EGF stimulation of the cells compared to parental cells. OP treatment of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently abated the cell viability with a LD50 of 7 and 4μM, respectively. Heterotopic xenografts of A2780 tumors developed abnormal bloody tumor vasculature in these mice. Anti-tumor activity of OP treatment at 50 mg/kg daily I.P. did not significantly impede A2780 tumor growth rate in a time-to-progression, but significantly cause a reduction of lung metastases compared with the untreated and OP 30 mg/kg cohorts. Silencing Snail in A2780 cells, but not the Slug KD member completely abrogated the tumor vascularization, growth and spread to the lungs in these mice. A2780 and A2780 Slug KD tumors expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial cells. These findings uncover a novel organizational signaling platform connecting the Snail-MMP-9 signaling axis in amplifying the Neu1-MMP-9 cross-talk in regulating EGF receptors, tumor neovascularization, growth and invasiveness.

Citation Format: Myron R. Szewczuk, Samar Abdulkhalek, Olivia Geen, Lacey Brodhagen, Fiona Haxho, Farah Alghamdi, Stephanie Allison, Duncan Simmons, Leah O'Shea, Ronald Neufeld. Transcriptional factor Snail and MMP-9 signaling axis amplifies Neu1-MMP-9 crosstalk on EGF receptor to regulate tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-274. doi:10.1158/1538-7445.AM2015-LB-274
Abstract LB-284: Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families
Authors: Kuusisto Kirsi M. , Rantapero Tommi , Kankuri-Tammilehto Minna , Nykter Matti , Laasanen Satu-Leena , Schleutker Johanna
Published: August 2015

Background: Breast cancer has a well-established genetic component. However, genetic predisposition factors remain mostly unresolved in high-risk hereditary breast cancer families that do not carry mutations in two major susceptibility genes, BRCA1 and BRCA2. In this study, we aimed to identify rare variants contributing to disease susceptibility in the high-risk Finnish BRCA1/2-negative hereditary breast or breast-ovarian cancer families by using family-based exome sequencing approach.

Methods: Germline DNA of 37 individuals from 13 high-risk hereditary breast or breast-ovarian cancer families was analyzed using targeted exome capture and massively parallel sequencing. Priority was given for rare (minor allele frequency<0.05) coding functional variants including nonsynonymous single nucleotide variants (SNVs), frameshift indels as well as stoploss/stopgain and splice-site variants. Candidate variants were selected based on the computational pathogenicity predictions by several tools and gene pathway analyses. Moreover, segregation of the variants with the disease was studied in the families. Candidate variants were confirmed by Sanger sequencing and genotyped in additional cohorts of breast cancer patients and healthy controls.

Results: Altogether 21,530 rare coding functional variants (97.0% nonsynonymous SNVs, 1.6% frameshift indels, 1.4% stoploss/stopgains variants) as well as 5 splice site variants were observed in 37 individuals. Of these, 93 novel variants, that harbor genes participating in the DNA damage response pathway, were prioritized. Furthermore, only variants that were predicted to be pathogenic, were considered and they were manually studied through literature. Altogether 20 candidate variants were selected for further segregation, validation, and genotyping experiments, which are currently ongoing.

Conclusions: Identified rare functional variants especially in the DNA damage response pathway genes can explain a fraction of the genetic predisposition to breast and ovarian cancer in the high-risk Finnish families.

Citation Format: Kirsi M. Kuusisto, Tommi Rantapero, Minna Kankuri-Tammilehto, Matti Nykter, Satu-Leena Laasanen, Johanna Schleutker. Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-284. doi:10.1158/1538-7445.AM2015-LB-284
Abstract LB-290: Multiple distinct mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma
Authors: Powers John T. , Tsanov Kaloyan M. , Roles Frederik , Ebright Richard , Seligson Marc , de Soysa Yvanka , Cahan Patrick , Theissen Jessica , LaPier Grace S. , Pearson Dan S. , Berthold Frank , Daley George Q.
Published: August 2015

The let-7 microRNA family are known tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma, a neural crest derived tumor, is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has recently been implicated as a critical regulator of MYCN, but we have employed siRNA and CRISPR-mediated gene disruption to show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN-amplified neuroblastoma cell lines despite robust de-repression of let-7, which prompted us to explore additional mechanisms for let-7 disruption. Consequently, we have found that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-class of self-sponging amplified-competing-endogenous-RNA (aceRNA), which reconciles the dispensability of LIN28B in NB cell lines. In addition, by analyzing a large cohort of tumor samples from patients, we observe frequent genomic loss of let-7 that inversely associates with MYCN-amplification, providing a functional explanation for the known MYCN-amplification-independent pattern of chromosome 3p and 11q loss, which harbor let-7g and let-7a2, respectively. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN-amplified tumors marks decreased survival, further underscoring its importance. The inverse selective relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis.

Note: This abstract was not presented at the meeting.

Citation Format: John T. Powers, Kaloyan M. Tsanov, Frederik Roles, Richard Ebright, Marc Seligson, Yvanka de Soysa, Patrick Cahan, Jessica Theissen, Grace S. LaPier, Dan S. Pearson, Frank Berthold, George Q. Daley. Multiple distinct mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2015-LB-290
Abstract LB-291: microRNA regulation of Nrf2: A link between autophagy and oxidative stress
Authors: Pokrzywinski Kaytee L. , Rao V. Ashutosh
Published: August 2015

Understanding the relationship between autophagy and excessive oxidative stress is crucial for determining the fate of cancer cells exposed to redox-active chemotherapeutic agents. Previous studies have shown that Mitoquinone (MitoQ), a redox active, mitochondrialy targeted ubiquinone derivative, can induce autophagy through the generation of excess reactive oxygen species and stimulate the antioxidant response involving nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in breast cancer cells. Nrf2 is a transcription factor that is up-regulated during oxidative stress and activates the antioxidant response element, which in turn regulates antioxidant expression. The aim of this study was to evaluate microRNA (miRNA) as a link between oxidative stress and autophagy through modulation of Nrf2 activity. miRNA are endogenous 18-22 bp double stranded RNA that become active when bound to the 3′ UTR of target messenger RNA (mRNA). The primary goal was to suppress Nrf2 activity with miRNA so that oxidative stress, in the absence of antioxidants, can result in apoptosis rather than autophagy. miRNA expression was evaluated using Illumina RNA sequencing analyses in MDA-MB-231 human breast cancer cells after treatment with DMSO or MitoQ (5 μM), in the presence and absence of Nrf2 silencing RNA (siRNA). Preliminary results show that Nrf2 is the most active at or before 18hrs of treatment (tested up to 72hrs) accompanied by a significant increase in nuclear Nrf2 levels. We are currently evaluating the transcriptome to identify key miRNAs that were up-regulated during Nrf2 suppression and down-regulated during Nrf2 activation. Nrf2 activity was also assessed using a stably transfected GFP modified MDA-MB-231 cell line containing the 3′ UTR region of Nrf2. Prior to obtaining the transcriptome, preliminary Nrf2-miRNA tests were performed with miR-93 as this miRNA has been shown to regulate Nrf2 expression in other studies on human breast cancer cell lines. We are currently assessing the effect of miR-93 on Nrf2 regulation, autophagy and apoptosis to decipher how miR-93 and other microRNA regulate Nrf2 signaling following excessive oxidative stress.

Citation Format: Kaytee L. Pokrzywinski, V. Ashutosh Rao. microRNA regulation of Nrf2: A link between autophagy and oxidative stress. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2015-LB-291
Abstract LB-292: Epigenetic downregulation of ABCG2 in colorectal cancer by a novel microRNA-DNA methylation mechanism - an attractive target for cancer prevention
Authors: To Kenneth K.W. , Leung Wing Wah , Ng Simon S.M.
Published: August 2015

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. It develops in a complex multi-step process. The majority of studies to date have focused on genetic mutations and epigenetic changes that drive the CRC carcinogenesis process. Xenobiotic transporters play an important role in safeguarding our body from external toxic substances. These transporters lining the gastrointestinal tract may thus protect us from the dietary carcinogens. This study aims to investigate the downregulation of an efflux transporter ABCG2 in colorectal cancer versus normal colon mucosa, so as to shed some light on its relevance to CRC initiation and progression. We found that ABCG2 expression is at least 50-fold lower in adenomatous polyps and colon carcinoma specimens obtained from CRC patients than in their matched pair of adjacent normal colon mucosa. This may facilitate the accumulation of genotoxins to propel tumor initiation and progression. The underlying mechanism(s) for ABCG2 under-expression in CRC is currently not known. To this end, aberrant promoter methylation of ABCG2 has been reported to cause its repression in a few cancer types including renal carcinoma and multiple myeloma. On the other hand, ABCG2 promoter demethylation has been reported to upregulate the transporter to mediate multidrug resistance in lung cancer and acute lymphoblastic leukemia. In this study, miR-203 was found to be downregulated in all polyps and CRC specimens, relative to adjacent normal colon mucosa. We demonstrated that the de novo DNA methyltransferase DNMT3 is a direct target of miR-203. Importantly, by relieving the repression on DNMT3, the lower expression of miR-203 in CRC caused remarkable ABCG2 promoter methylation and lower ABCG2 expression in colon cancer cell lines and the patient CRC specimens. In spite of the complex sequential genetic mutations and epigenetic changes leading to CRC formation, we proposed that the restoration of the xenobiotic transporter ABCG2 function via modulating this new microRNA-DNA methylation mechanism in precancerous cells may represent an attractive strategy to stop or delay the carcinogenesis process.

Citation Format: Kenneth K.W. To, Wing Wah Leung, Simon S.M. Ng. Epigenetic downregulation of ABCG2 in colorectal cancer by a novel microRNA-DNA methylation mechanism - an attractive target for cancer prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-292. doi:10.1158/1538-7445.AM2015-LB-292
Abstract LB-294: Cellular microRNAs whose expression is altered by the oncogenic mouse polyomavirus
Authors: Chokkalingam Neethu , Sung Chang K.
Published: August 2015

microRNAs are non-coding small RNAs that regulate expression of many genes and have been proposed as useful biomarkers for diverse diseases including cancer. Studies of the highly oncogenic mouse polyomavirus (Py) have identified many pathways in tumor development. The pathways found altered in Py-induced tumors strongly overlap with those affected in various human cancers, highlighting the Py-mouse systems's broad applicability to oncology. In spite of the resolving power of microRNA expression analysis and the relevance of the oncogenic mouse virus to human cancer, currently there is a lack of systematic profiling analysis on microRNAs in the context of the early phases of Py-induced tumor development and progression. We focused our investigation on cellular microRNAs that may be targeted by Py during viral infection for possible microRNA biomarkers of oncogenesis. To explore the effects of Py infection on the host microRNA expression and to identify those microRNAs that are functionally involved in Py-induced tumorigenesis, microRNA expression in uninfected and Py-infected mouse cells were compared using the microRNA Array kit. This qRT-PCR based screening and further validation assays revealed that the levels of seven murine microRNAs were elevated in Py-infected cells which include miR-let7a, miR-32, miR-124, miR-141, miR-146a, miR-215, and miR-218.Our further research focuses on identification of genes targeted by these microRNAs and their roles during viral infection. This study will bring a better understanding of microRNA involvement in tumor development, progression and possibly prevention.

Citation Format: Neethu Chokkalingam, Chang K. Sung. Cellular microRNAs whose expression is altered by the oncogenic mouse polyomavirus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-294. doi:10.1158/1538-7445.AM2015-LB-294
Abstract NG07: Immunomodulatory and tumor cell killing effects of the demethylating agent 5-azacytidine in ovarian cancer
Authors: Chiappinelli Katherine B. , Strissel Pamela , Yen Ray-Whay Chiu , Li Huili , Stone Meredith L. , Murphy Lauren , Akman Benjamin , Zahnow Cynthia A. , Strick Reiner , Baylin Stephen B.
Published: August 2015

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Citation Format: Katherine B. Chiappinelli, Pamela Strissel, Ray-Whay Chiu Yen, Huili Li, Meredith L. Stone, Lauren Murphy, Benjamin Akman, Cynthia A. Zahnow, Reiner Strick, Stephen B. Baylin. Immunomodulatory and tumor cell killing effects of the demethylating agent 5-azacytidine in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr NG07. doi:10.1158/1538-7445.AM2015-NG07
Abstract PL02-04: Drastically reducing HPV-associated cancers through etiologically-based primary and secondary prevention
Authors: Lowy Douglas R.
Published: August 2015

HPV infection causes more than 25,000 anogenital and oropharyngeal cancers annually in US men and women and is responsible for about 10% of all female cancers worldwide. In the developing world, where cervical cancer is the main HPV-associated cancer, a woman's lifetime risk of dying from this cancer is estimated to be about 1%. Persistent infection by more than 10 HPV types can lead to cervical cancer; HPV16 and HPV18 account for about 70% of these tumors. These two HPV types account for more than >90% of the HPV-positive non-cervical cancers. Primary prevention by the FDA-approved HPV vaccines has the potential to reduce the incidence and mortality attributable to the HPV-positive anogenital and oropharyngeal cancers, while secondary prevention through HPV-based screening for cervical cancer can lower the incidence and mortality for this cancer. The first generation virus-like particle HPV vaccines, which target HPV16 and HPV18, can prevent more than 90% of new persistent infections attributable to these HPV types. These vaccines are already having an impact on HPV-induced early disease markers in vaccinated populations, including evidence of herd immunity. The high immunogenicity of these vaccines suggests that it should be possible to safely reduce the number of recommended vaccine doses from three to two - and perhaps eventually even to one dose - in young adolescents, who represent the main target group for the vaccine. A second generation vaccine, which targets the seven most oncogenic HPV types and has the potential to prevent ∼90% of cervical cancer, was recently approved by the FDA. HPV-based testing was recently approved by the FDA for primary cervical cancer screening in women 25 or older. Compared to cytology-based screening, HPV-based testing has higher sensitivity for detecting infections that may lead to squamous cell carcinoma and adenocarcinoma. It is predicted that the greater sensitivity of HPV-based testing will be even more important for cervical cancer screening of vaccinated women.

Citation Format: Douglas R. Lowy. Drastically reducing HPV-associated cancers through etiologically-based primary and secondary prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr PL02-04. doi:10.1158/1538-7445.AM2015-PL02-04
Abstract RAOS15-03: Pancreatic tumor stroma as a therapeutic target
Authors: Evans Ronald M.
Published: August 2015

Pancreatic ductal adenocarcinoma (PDAC) occurs in the context of an exuberant desmoplastic response that produces a ‘living chimera’ of tumor and activated stromal components. A prominent feature of the stromal response is the transformation of the Vitamin A storing pancreatic stellate cell (PSC) to activated myofibroblasts. We hypothesized that restoration of the quiescent PSC phenotype could disrupt tumor-stroma crosstalk and thus improve response to chemotherapy. Recently, we have shown that the vitamin D receptor (VDR) is expressed at high levels in activated human pancreatic tumor stroma and, in response to ligand, acts as a master transcriptional regulator of PSCs to reprise the quiescent state. In vivo, a synthetic VDR agonist (Cal) induced signal-dependent transcriptional remodeling of tumor stroma, enhancing the anti-tumor effects of gemcitabine by increasing intra-tumoral concentration 5-fold to reduce tumor growth. A survival study in KPC mice shows that addition of CAL results in a 57% increase in lifespan relative to Gemcitabine treatment alone. An approved IND enables the exploration of CAL in the neo-adjuvant setting in patients with resectable PDAC. This Phase I trial is designed to establish whether CAL (Zemplar) is able to reach the tumor and alter genes and other measurable responses linked to stromal reprogramming.

Citation Format: Ronald M. Evans. Pancreatic tumor stroma as a therapeutic target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr RAOS15-03. doi:10.1158/1538-7445.AM2015-RAOS15-03
Abstract SY04-03: Molecular networks defining cell identity
Authors: Daley George Q.
Published: August 2015

Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages represent powerful approaches to engineering cell identity for applications in research and regenerative medicine. I will describe CellNet, a network biology platform developed to assess the fidelity of cellular engineering and to generate specific hypotheses for improving cell derivations. Analyzing published accounts, we have confirmed that reprogramming to pluripotency is remarkably robust, and found that cells derived via directed differentiation more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell type gene regulatory networks. We have applied CellNet to two cell fate conversion paradigms: conversion of B cells to macrophages and fibroblasts to hepatocyte-like cells, and learned provocative new lessons about the nature of these engineered cells. CellNet analysis, iteratively coupled to experimental validation, provides a rational strategy to enhance the derivation of target cells for research and therapy.

Citation Format: George Q. Daley. Molecular networks defining cell identity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY04-03. doi:10.1158/1538-7445.AM2015-SY04-03
Abstract SY07-04: The evolutionary landscape of CLL: Therapeutic implications
Authors: Wu Catherine J.
Published: August 2015

Clonal evolution is a key feature of cancer progression and relapse. Recent studies across cancers have demonstrated the extensive degree of intratumoral heterogeneity present within individual cancers. We hypothesized that evolutionary dynamics contribute to the variations in disease tempo and response to therapy that are highly characteristic of chronic lymphocytic leukemia (CLL). We have recently investigated this phenomenon by developing a pipeline that estimates the fraction of cancer cells harboring each somatic mutation within a tumor through integration of whole-exome sequence (WES) and local copy number data (Landau et al., Cell 2013). By applying this analysis approach to 149 CLL cases, we discovered earlier and later cancer drivers, uncovered patterns of clonal evolution in CLL and linked the presence of subclones harboring driver mutations with adverse clinical outcome. Thus, our study, generated from a heterogeneous sample cohort, strongly supports the concept that CLL clonal evolution arises from mass extinction and therapeutic bottlenecks which lead to the emergence of highly fit (and treatment resistant) subclones. We further hypothesized that epigenetic heterogeneity also shapes CLL clonal evolution through interrelation with genetic heterogeneity. Indeed, in recent work, we have uncovered stochastic methylation disorder as the primary cause of methylation changes in CLL and cancer in general, and that this phenomena impacts gene transcription, genetic evolution and clinical outcome. Thus, integrated studies of genetic and epigenetic heterogeneity in CLL have revealed the complex and diverse evolutionary trajectories of these cancer cells.

Immunotherapy is exquisitely suited for specifically and simultaneously targeting multiple lesions. We have developed an approach that leverages whole-exome sequencing to systematically identify personal tumor mutations with immunogenic potential, which can be incorporated as antigen targets in multi-epitope personalized therapeutic vaccines. We are pioneering this approach in an ongoing trial in melanoma and will now expand this concept to address diverse malignancies. Our expectation is that the choice of tumor neoantigens for a vaccine bypasses thymic tolerance and thus generates highly specific and potent high-affinity T cell responses to eliminate tumors in any cancer, including both ‘trunk’ and ‘branch’ lesions.

Citation Format: Catherine J. Wu. The evolutionary landscape of CLL: Therapeutic implications. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY07-04. doi:10.1158/1538-7445.AM2015-SY07-04
Abstract SY09-04: Cancer crosstalk: miR-200-containing extracellular vesicles promote breast cancer cell metastasis
Authors: Lieberman Judy , Le Minh
Published: August 2015

Metastasis is the major cause of death of breast cancer patients. Not all cancer cells within a tumor are capable of metastasizing. The microRNA-200 (miR-200) family, which regulates the mesenchymal-to-epithelial transition, is enriched in the serum of patients with metastatic cancers. Ectopic expression of miR-200 can confer metastatic ability to poorly metastatic tumor cells in some settings. Here, we investigated whether metastatic capability could be transferred between metastatic and nonmetastatic cancer cells via extracellular vesicles. miR-200 was secreted in extracellular vesicles from metastatic murine and human breast cancer cell lines, and miR-200 levels were increased in sera of mice bearing metastatic tumors. In culture, murine and human metastatic breast cancer cell extracellular vesicles transferred miR-200 microRNAs to nonmetastatic cells, altering gene expression and promoting mesenchymal-to-epithelial transition. In murine cancer and human xenograft models, miR-200-expressing tumors and extracellular vesicles from these tumors promoted metastasis of otherwise weakly metastatic cells either nearby or at distant sites and conferred to these cells the ability to colonize distant tissues in a miR-200-dependent manner. Together, our results demonstrate that metastatic capability can be transferred by the uptake of extracellular vesicles.

Citation Format: Judy Lieberman, Minh Le. Cancer crosstalk: miR-200-containing extracellular vesicles promote breast cancer cell metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY09-04. doi:10.1158/1538-7445.AM2015-SY09-04
Abstract SY13-03: Novel targeted therapies in myelodysplastic syndrome
Authors: Ebert Benjamin
Published: August 2015

Ubiquitin ligases target specific proteins for degradation, and pharmacologic modulation of ubiquitin ligase activity has the potential for therapeutic efficacy in cancer by altering the abundance of proteins that are required for tumor cell survival. Thalidomide and its derivatives, lenalidomide and pomalidomide, represent the first class of drugs that act by binding and changing the activity of a specific ubiquitin ligase. These compounds bind the CRL4-CRBN ubiquitin ligase, inducing the ubiquitination and consequent degradation of specific protreins. Lenalidomide is a highly effective drug for the treatment of myelodysplastic syndrome (MDS) with del(5q), multiple myeloma, and some additional B cell lymphomas. In multiple myeloma cells, lenalidomide increases the binding of two substrates, IKZF1 and IKZF3, to the CRBN substrate adapter; increases the ubiquitination of these substrates; and causes the targeted degradation of IKZF1 and IKZF3, transcription factors that are essential for the differentiation and survival of plasma cells including multiple myeloma cells. In del(5q) MDS, lenalidomide targets CSNK1A1 for destruction. Haploinsufficiency for CSNK1A1, a gene located within the common deleted region on chromosome 5q, results in selective targeting of the del(5q) clone. Recent studies indicate that lenalidomide, pomalidomide, and thalidomide modulate the CRl4-CRBN ubiquitin ligase in distinct ways, raising the possibility that new molecules may induce degradation of other proteins, creating new therapeutic opportunities.

Citation Format: Benjamin Ebert. Novel targeted therapies in myelodysplastic syndrome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2015-SY13-03
Abstract SY16-03: Enterprise-wide clinical sequencing to match patients to personalized cancer treatments
Authors: Berger Michael F.
Published: August 2015

Massively parallel sequencing of tumors enables the identification of oncogenomic mutations that correlate with response and resistance to targeted therapies and the prospective detection of these biomarkers in patients with cancer. At Memorial Sloan Kettering Cancer Center, we have developed and optimized a targeted sequencing panel encompassing more than 300 key cancer associated genes (MSK-IMPACT), which we have applied to prospectively profile several thousands of tumors in the clinical setting. The large-scale implementation of our clinical assay has allowed us to identify targetable mutations in patients with many types of cancer and to match patients to the most appropriate clinical trials. I will discuss general challenges and considerations involved in the establishment of an infrastructure for precision oncology at a large center, including challenges in the analysis and management of data and the clinical interpretation of genomic results. I will also present results from our molecular profiling initiative, including several cases in which they have directly influenced patient management.

Citation Format: Michael F. Berger. Enterprise-wide clinical sequencing to match patients to personalized cancer treatments. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY16-03. doi:10.1158/1538-7445.AM2015-SY16-03
Abstract SY19-01: Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy
Authors: Lee Michael J. , Dayma Yogesh , Heijinks Anne-Margriet , Morton Stephen W. , Dreaden Erik C. , Hammond Paula T. , Yaffe Michael B.
Published: August 2015

Dynamic re-wiring of signaling networks is a prominent mechanism responsible for the development of resistance to many molecular-targeted anti-cancer agents. Here we show how this same dynamic re-wiring process can be used therapeutically to enhance the response of tumors to cytotoxic anti-cancer agents. Using cell lines and murine tumor models of triple-negative breast cancer, non-small cell lung cancer, and head and neck cancer, we show that chronic inhibition of EGFR and/or FGFR driver oncogenes dramatically enhances cell death in response to topoisomerase inhibitors and platinum DNA crosslinking drugs. In marked contrast, no such sensitization is observed when the growth factor receptor inhibitors are co-administered with the cytotoxic agents. The molecular mechanism responsible for this time-dependent growth factor inhibitor-induced tumor cell sensitization was explored using a systems biology-based model of DNA damage signaling in which protein kinase activities, substrate phosphorylation, and phosphoprotein-binding events for multiple signaling pathways were quantitatively measured at densely sampled points in time, and mathematically correlated with tumor cell responses including cell cycle arrest, cytokine production, autophagy, and apoptosis. This analysis revealed that sustained EGFR/FGFR suppression unmasks an apoptotic network involving Caspase-8 that is normally suppressed by oncogene addiction, resulting in an enhanced apoptotic response to equivalent amounts of DNA damage. This discovery demonstrates that the timing interval between administration of different drugs in combination chemotherapy can have profound effects on the tumor response through the dynamic re-wiring of cell signaling pathways in real time. Finally, we take advantage of this dynamic re-wiring process by developing tumor-targeted time-staggered release nanoparticles that deliver EGFR inhibitors at early times followed by the delayed release of doxorubicin. We show that these nanoparticles cause dramatic regression of murine NSCLC and TNBC tumor xenografts in vivo, substantiating the utility of therapeutic network re-wiring for anti-cancer therapy in the clinic.

Citation Format: Michael J. Lee, Yogesh Dayma, Anne-Margriet Heijinks, Stephen W. Morton, Erik C. Dreaden, Paula T. Hammond, Michael B. Yaffe. Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2015-SY19-01
Abstract SY20-01: Conventional chemotherapy cures people by exploiting apoptotic priming
Authors: Letai Anthony G.
Published: August 2015

Conventional chemotherapy has an amazing track record that is often under-appreciated in today's world of genomics and targeted pathway inhibitors. Conventional chemotherapy is responsible for curing millions of cancer patients over the past 5 decades. That is, millions of patients have presented to their doctors with an otherwise fatal malignancy, were given a finite course of chemotherapy (largely DNA and microtubule perturbing agents) and had their cancer eradicated, never to return. Perhaps as remarkable as the magnitude of the achievement of conventional chemotherapy is the magnitude of our ignorance of why it should ever work, and why it works far better in some tumors than in others. Textbook explanations rely on concepts of differential proliferation rates in cancers that are incompletely supported in the clinical literature. Successful chemotherapy treatments usually kill via the mitochondrial pathway of apoptosis. We have found that simple functional measurements of the pre-treatment state of the tumor cell can be rapidly made with BH3 profiling. These measurements demonstrate that a major, if not the major, reason for a therapeutic index for cancer chemotherapy is that chemo-sensitive cancer cells are simply more primed for apoptosis than normal cells. Moreover, apoptotic priming can be measured to make clinical predictions regarding quality of response on an individualized basis. Enhancing pretreatment priming of cancer cells with selectively acting targeted agents is a promising strategy to extend the demonstrated curative power of conventional chemotherapy.

Citation Format: Anthony G. Letai. Conventional chemotherapy cures people by exploiting apoptotic priming. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY20-01. doi:10.1158/1538-7445.AM2015-SY20-01
Abstract SY23-03: Intratumoural heterogeneity in human serous ovarian carcinoma
Authors: Stingl John P.
Published: August 2015

To investigate the hierarchical organization of cells within human high grade serous ovarian carcinomas (HGSOC), we used a combination of multi-parameter flow cytometry and in vitro and in vivo functional assays to interrogate the growth and differentiation properties of phenotypically distinct cell populations present within 86 freshly isolated, non-cultured HGSOC tissues. Our results indicate that 3 functionally distinct subpopulations of epithelial cells can be identified. One population expresses high levels of the epithelial cell protein EpCAM, whereas the other two populations are EpCAM-, but express podoplanin (PDPN) and variable levels of CD34. All detectable growth in vitro colony-forming cell and sphere-forming assays is restricted to the two EpCAM- cell populations, although the types of progeny the two EpCAM- subpopulations differ from one another. Xenotransplantation of lentivirally marked HGSOC cell subpopulations into immune-deficient mice reveals that in vivo engrafting ability is restricted to only EpCAM-PDPN+CD34- cells. Treatment of mice harbouring HGSOC xenografts with cisplatin reveals that non-cycling EpCAM- cells appear to have a selective survival advantage during the course of chemotherapy.

Citation Format: John P. Stingl. Intratumoural heterogeneity in human serous ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY23-03. doi:10.1158/1538-7445.AM2015-SY23-03