bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 906: Therapeutic potential of JAK/STAT signal inhibition in prostate cancer by the JAK inhibitor AZD1480.
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Nozawa Masahiro , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu
Published: August 2014

Signal transducers and activators of transcription (STAT) were originally identified as components of cytokine signal transduction pathways but are now also recognized as key regulators of apoptosis, proliferation, angiogenesis and immune responses in many malignant diseases. Activation of STAT3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/ STAT3 signaling pathway. Of these cytokines, interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors. Activated IL-6 has also been shown to be elevated in the sera from patients with metastatic prostate cancer, and persistent activation of STAT3 is a common feature. To better characterize the potential role of JAK/STAT3 as a therapeutic target for advanced prostate cancer, we used the JAK1/2 inhibitor, AZD1480 to suppress the transcriptional activation of STAT3 in a PTEN-conditional knockout mouse model of prostate cancer. Prostate tumors from homozygous PTEN-mutant mice share many characteristics of human prostate cancer, including increased activation of the JAK/STAT3 signaling cascade. Our pharmacodynamic studies show that AZD1480 elicited a strong inhibition of STAT3 signal activation leading to decreased tumor cell proliferation, and induction of apoptosis. Our drug intervention studies show that persistent suppression of STAT3 signaling results in a reduction of tumor growth characterized by a decrease in tumor cell proliferation, induction of apoptosis, and decreased angiogenesis. However, PI3K/Akt and MAPK signaling were upregulated in response to STAT3 signal inhibition. Our findings show a strong antitumor effect for STAT3 signal inhibition and may be a promising therapeutic option for prostate cancer; however, it still requires further optimization in order to maximize its clinical potential.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Therapeutic potential of JAK/STAT signal inhibition in prostate cancer by the JAK inhibitor AZD1480. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 906. doi:10.1158/1538-7445.AM2013-906
Abstract 913: Natural product sulforaphane selectively inhibits breast cancer stem cells in basal and trastuzumab resistant Her2+ breast cancer.
Authors: Burnett Joseph , Korkaya Hasan , Newman Bryan , Conley Sarah , Connarn Jamie , Sun Lichao , Lee Hsiu-Fang , Ouzounova Maria , Wicha Max , Sun Duxin
Published: August 2014

The natural product sulforaphane (SF) has demonstrated efficacy against multiple forms of cancers and cancer stem cells. However, it is unclear what are the molecular targets for sulforaphane to inhibit breast cancer stem cells and how efficacy varies among four subtypes of breast cancers. In vitro assay showed that sulforaphane preferentially inhibited triple negative (TNBC) breast cancers, but did not show any efficacy to inhibit Her2+ breast cancer cells (even at >100 uM). However, when Her2+ breast cancer cells (with PTEN deletion) developed resistance to trastuzumab, sulforaphane showed more than 20-fold higher activity. Low concentration of sulforaphane (1 uM) also preferentially eliminates breast cancer stem cells from triple negative breast cancers. Her2+ breast cancer cells (with PTEN deletion and long term treatment of trastuzumab) induced resistance to trastuzumab and increase breast cancer stem cell populations by activating a positive feedback loop of IL-6 and NF-kB. Luciferase reporter assay and immunostaining showed that sulforaphane (1 uM) disrupted NF-kB translocation from cytosol to nucleus and inhibited its activity. Sulforaphane (1 uM) also inhibited endogenous IL-6 production by 50%. Sulforaphane (50 mg/kg, adjuvant therapy) reduced tumor formation rate by 70% and inhibit tumor volume by more than 90% of trastuzumab resistant Her2+ breast cancers in mouse fat pad. These data suggest that sulforaphane inhibits trastuzumab-resistant Her2+ breast cancers and breast cancer stem cells by disrupting NF-kB and IL6 positive feedback loop.

Citation Format: Joseph Burnett, Hasan Korkaya, Bryan Newman, Sarah Conley, Jamie Connarn, Lichao Sun, Hsiu-Fang Lee, Maria Ouzounova, Max Wicha, Duxin Sun. Natural product sulforaphane selectively inhibits breast cancer stem cells in basal and trastuzumab resistant Her2+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 913. doi:10.1158/1538-7445.AM2013-913
Abstract 918: ASP3026, a selective ALK inhibitor, shows anti-tumor activity in a mouse model xenografted with NCI-H2228 intracranially.
Authors: Konagai Satoshi , Fushiki Hiroshi , Sakagami Hideki , Ueno Yoko , Mori Masamichi , Shimada Itsuro , Kondoh Yutaka , Miyoshi Sousuke , Nishimura Shintaro , Kuromitsu Sadao
Published: August 2014

EML4-ALK translocation has been validated as a therapeutic target in a subset of non-small cell lung cancer (NSCLC) patients. Crizotinib, an FDA-approved ALK inhibitor, is effective against several types of human cancers with ALK abnormalities including EML4-ALK, RANBP2-ALK and ALK mutations. However, long-term treatment is often limited by the development of resistant tumors and distant metastases. Multiple brain metastases are a critical issue because of their poor prognosis despite the standard radiotherapy. The reason for metastases and development of tumor in the brain could be attributable to the poor penetration of crizotinib into central nervous system, as previously reported. ASP3026 is a selective ALK inhibitor which shows antitumor activities in several crizotinib-refractory models including gate keeper mutants.

Here, we established an intracranial xenograft model by implanting NCI-H2228 cells directly in the brain of immunocompromised mice. Xenografted cells develop intracranial tumors which grow in murine brain and eventually become lethal, resembling the clinical tumors that metastasized in the brain.

To determine the anti-tumor activity against tumors in the brain, mice were treated with ASP3026 or crizotinib for 2 weeks and held to observe survival duration. Ten, 30 and 100 mg/kg daily oral administration of ASP3026 dose dependently inhibited tumor growth in brain, and tumor regression was achieved in 30 and 100 mg/kg groups confirmed by MR imaging. These results were supported by the observation that Ktrans and IAUC (90s) were significantly decreased in 30 and 100 mg/kg groups using dynamic contrast enhanced MR imaging (DCE-MRI). Furthermore, ASP3026 significantly prolonged the survival of tumor bearing mice compared to vehicle treatment group. On the other hand, 30mg/kg daily oral administration of crizotinib inhibited the tumor growth during the treatment period but did not produce significant survival benefit.

Taken together, these results indicate that ASP3026 shows better efficacy than crizotinib and improves overall survival in an intracranial mouse xenograft model, suggesting that ASP3026 may have potential to benefit EML4-ALK positive NSCLC patients with brain metastases.

Citation Format: Satoshi Konagai, Hiroshi Fushiki, Hideki Sakagami, Yoko Ueno, Masamichi Mori, Itsuro Shimada, Yutaka Kondoh, Sousuke Miyoshi, Shintaro Nishimura, Sadao Kuromitsu. ASP3026, a selective ALK inhibitor, shows anti-tumor activity in a mouse model xenografted with NCI-H2228 intracranially. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 918. doi:10.1158/1538-7445.AM2013-918
Abstract 94: Identifying biomarkers of estrogen response in models of serous ovarian cancer.
Authors: Andersen Courtney L. , Sikora Matthew J. , Haluska Paul , Oesterreich Steffi
Published: August 2014

Ovarian cancer is the fifth leading cause of cancer death among women in the United States. Despite advances in treatment for other cancers, ovarian cancer patient prognosis has not improved significantly since the advent of platinum-based chemotherapy. It is a highly heterogeneous disease with at least four distinct histological subtypes: serous, mucinous, endometrioid, and clear cell. However, no subtype- or biomarker-specific therapies are approved for ovarian cancer. Identifying targeted therapies is crucial to improving clinical outcomes. Specific therapies will likely vary based on tumor histology and biomarkers.

Expression of estrogen receptor alpha (ER) is a well established biomarker of response to endocrine therapies in breast cancer. Despite the success of anti-estrogen therapies in treating breast cancer, little attention has been given to their potential in ovarian cancer. However, epidemiologic studies show that approximately 70% of epithelial ovarian tumors express ER, particularly serous and endometrioid subtypes, and that estrogen plays a role in ovarian cancer etiology. Further, clinical data suggest that a subset of ovarian cancer patients can be successfully treated with endocrine therapy. We hypothesize that some ovarian tumors require estrogen for growth and that predictive biomarkers will identify patients who will benefit from endocrine therapy.

Using cell line models, we examined the response of ovarian cancer cells to estrogen (E2) and anti-estrogens with regard to gene expression and cell proliferation. E2 induces expression of canonical ER target genes (e.g. GREB1) in these cells, suggesting that they are estrogen-responsive. We observe that 4-hydroxytamoxifen and fulvestrant inhibit growth of ovarian cancer cells including the chemo-resistant line PEO4. Gene expression microarray studies identified additional E2-regulated genes in ovarian cancer cells that may be utilized as biomarkers of ER activity. We are expanding our studies to in vivo models (human primary tumor xenografts) to evaluate the role of E2 in driving tumor progression and determine the efficacy of anti-estrogens in treating serous ovarian cancer.

There is a critical need for targeted therapies in ovarian cancer. Our studies will determine if endocrine responsiveness correlates with gene expression of specific biomarkers, which may lead to the identification of predictive clinical markers of response to endocrine therapy.

Citation Format: Courtney L. Andersen, Matthew J. Sikora, Paul Haluska, Steffi Oesterreich. Identifying biomarkers of estrogen response in models of serous ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 94. doi:10.1158/1538-7445.AM2013-94
Abstract 949: miR-634 restores drug sensitivity in tumor cells derived from patients with terminal drug-resistant ovarian cancer.
Authors: van Jaarsveld Marijn TM , van Kuijk Patricia F. , Boersma Antonius WM , Helleman Jozien , van Ijcken Wilfred F. , Mathijssen Ron HJ , Pothof Joris , Berns Els MJJ , Verweij Jaap , Wiemer Erik AC
Published: August 2014

The development of drug resistance is still a major impediment for the successful treatment of cancer. This is particularly pressing in the case of advanced ovarian cancer, which has a 5-year survival rate of 30%. Ovarian cancer is treated with paclitaxel and platinum (e.g cisplatin or carboplatin) combination chemotherapy. Despite an initial high chemo-responsiveness, most ovarian cancer patients will relapse and ultimately die of drug-resistant disease. The molecular processes that contribute to resistance have been extensively studied, however, not much is known about the role of microRNAs (miRNAs), small non-coding RNAs that regulate gene expression.

We compared miRNA expression profiles of isogenic cisplatin sensitive and resistant cell line pairs. The only miRNA that was consistently downregulated in all three resistant cell lines was miR-634 (FDR<1%). Overexpression of miR-634 in ovarian cancer cell lines gave rise to a minor, but reproducible, cell cycle block and reduced cellular viability by 20-50%. In addition, miR-634 transfection resensitized cisplatin-resistant ovarian cancer cell lines. We next investigated whether miR-634 overexpression could enhance therapy response in a more clinical setting. We isolated and cultured tumor cells from 7 patients that had become refractory to carboplatin-paclitaxel combination chemotherapy. We show that miR-634 overexpression causes a ∼two-fold decrease in IC50 for cisplatin and carboplatin treatment. In addition, a ∼1.3-fold decrease in doxorubicin sensitivity was observed upon miR-634 overexpression. Finally, overexpression of miR-634 resulted in downregulation of its predicted targets Cyclin D1 and GRB2, ERK2, RSK1 and RSK2, components of the Ras-MAPK pathway. The combined effect on these miR-634 targets may explain the effects on the cell cycle, cellular viability and response to chemotherapy.

Altogether, our findings suggest that miR-634 modulates important cancer relevant targets and that raising miR-634 levels can be a means to resensitize chemotherapy resistant ovarian tumors.

Citation Format: Marijn TM van Jaarsveld, Patricia F. van Kuijk, Antonius WM Boersma, Jozien Helleman, Wilfred F. van Ijcken, Ron HJ Mathijssen, Joris Pothof, Els MJJ Berns, Jaap Verweij, Erik AC Wiemer. miR-634 restores drug sensitivity in tumor cells derived from patients with terminal drug-resistant ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 949. doi:10.1158/1538-7445.AM2013-949
Abstract 952: Stemofoline is a potent natural product modulator of the multidrug resistance-linked P-glycoprotein (ABCB1).
Authors: Ohnuma Shinobu , Chanmahasathien Wisinee , Miura Koh , Unno Michiaki , Abudkar Suresh V. , Limtrakul Pornngarm
Published: August 2014

Background: Stemofoline is a plant alkaloid isolated form Stemona, which is native to southeastern Asia. P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter superfamily is implicated in multidrug resistance (MDR) in cancer cells. Aim: To investigate the effect of stemofoline on Pgp function.

Methods and Results: Stemofoline stimulated Pgp-mediated ATP hydrolysis (conc. required for 50% stimulation= 10-12, μM), suggesting that this alkaloid seems to interact with drug-binding site of Pgp. Consistent with this view, stemofoline inhibited the photo-crosslinking of Pgp with [125I]-iodoarylazidoprazosin (IAAP), which is a transport substrate. Interestingly, stemofoline instead of inhibiting verapamil-stimulated ATP hydrolysis, it further enhanced the ATPase activity suggesting that stemofoline and verapamil bind simultaneously to Pgp in the drug-binding pocket. In addition, the efflux of the fluorescent substrate calcein-AM from P-gp expressing cervical cancer cells (KB-V1) was blocked by stemofoline in a concentration-dependent manner.

Conclusion: These studies indicate that stemofoline could be developed as a potent modulator to overcome MDR in cancer cells.

Citation Format: Shinobu Ohnuma, Wisinee Chanmahasathien, Koh Miura, Michiaki Unno, Suresh V. Abudkar, Pornngarm Limtrakul. Stemofoline is a potent natural product modulator of the multidrug resistance-linked P-glycoprotein (ABCB1). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 952. doi:10.1158/1538-7445.AM2013-952
Abstract 963: Characterizing acquired resistance mechanisms to targeted therapy in FGFR1-amplified lung squamous cell carcinoma.
Authors: Liao Rachel G. , Sivachenko Andrey , Getz Gad , Dutt Amit , Hammerman Peter S. , Meyerson Matthew
Published: August 2014

Inhibitors targeting specific genomic alterations have revolutionized cancer therapy and dramatically improved patient outcomes; nonetheless, after a period response, patient tumors almost universally develop resistance to these inhibitors and recur. In the case of squamous cell carcinoma of the lung, it has been demonstrated that focal amplifications of the FGFR1 gene occur in at least 10% of patients and that a subset of these events are sensitive to FGFR targeted therapies. Here, we describe the generation of resistant clones of the cell line NCI-H2077 to several FGFR inhibitors with clinical potential. This cell line is a squamous lung line with a focal amplification of FGFR1 that demonstrates dependency in the presence of both small molecule inhibitors and knockdown of the FGFR1 protein. After generation of resistant clones, we performed RTK phosphorylation arrays in the presence and absence of inhibitor to determine whether there were changes in the activity of other kinases, and the lines were sequenced to determine whether secondary mutations in FGFR1 had arisen. Follow-up experiments were performed to determine alternative sensitivities of the resistant clones. These experiments contribute to our growing understanding of the resistance mechanisms that arise in response to kinase inhibitors, and it is our hope that they will benefit patients undergoing treatment for FGFR1-amplified lung squamous cell carcinoma.

Citation Format: Rachel G. Liao, Andrey Sivachenko, Gad Getz, Amit Dutt, Peter S. Hammerman, Matthew Meyerson. Characterizing acquired resistance mechanisms to targeted therapy in FGFR1-amplified lung squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 963. doi:10.1158/1538-7445.AM2013-963
Abstract 969: The anti-apoptotic impact of neurotrophic factor GDNF on breast cancer cells pre-treated with trastuzumab.
Authors: Gardaneh Mossa , Shojaei Sahar
Published: August 2014

Reports on breast cancer resistance to hormone/antibody therapy indicate molecular switches between membrane or non-membrane tyrosine kinase receptors may be key players. We investigated the impact of glial cell line-derived neurotrophic factor (GDNF) on the activity of these receptors in breast cancer cell lines pre-treated with trastuzumab that blocks her2. We found by RT-PCR and Western blot analyses that GDNF activates SRC via GDNF-specific receptor Ret leading to SRC-AKT interaction in the lipid raft of the cell membrane. Consequently, p53 is phosphorylated and interacts with MDM2 that ultimately inhibits apoptosis. Phosphorylation and activation events occurred more robustly in SKBR3, a cell line with strong her2 expression, than in MCF-7 and MDA-MB-231 both having lower expression levels of her2. Inhibition of the SRC-AKT interaction using an SRC-specific antibody blocked GDNF-promoted anti-apoptotic effects. We found similar changes when we replaced cell lines with her2-positive tumor cells collected from breast cancer patients. GDNF is introduced a molecular switch for promoting drug resistance in breast cancer therapy.

Citation Format: Mossa Gardaneh, Sahar Shojaei. The anti-apoptotic impact of neurotrophic factor GDNF on breast cancer cells pre-treated with trastuzumab. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 969. doi:10.1158/1538-7445.AM2013-969
Abstract 999: Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1β expression.
Authors: Huang Chi-Ruei , Yang Jhen-Hong , Chang Wen-Chang , Chen Ben-Kuen
Published: August 2014

The expression of cytokines, such as IL-1β, and the activation of the epidermal growth factor receptor (EGFR) are crucial regulators in the process of carcinogenesis. The correlation between growth factor and activated cytokine signals in the control of tumor development is a critical issue to be clarified. In our study, we found that the IL-1β gene and protein expression were induced by EGF in squamous cell carcinoma. To clarify the mechanism involved in EGF-regulated

IL-1β expression, we examined the transcriptional activity and mRNA stability of IL-1β in EGF-treated cells. We found that EGF induced the expression of IL-1β, and was mediated through transcriptional activation, but not through mRNA stability. The involvement of Akt and NF-κB signaling pathways in the EGF-induced IL-1β gene expression and promoter activity was confirmed by treating cells with Akt and NF-κB inhibitors, LY294002 and parthenolide, respectively. Using immunofluorescence staining assay, the EGF-stimulated nuclear translocation of NF-κB (p65) was inhibited by pre-treating cells with

LY294002 and parthenolide. Furthermore, EGF increased the binding of NF-κB to the NF-κB binding site of the IL-1β promoter through the activation of the Akt/NF-κB pathway, which resulted in activating IL-1β promoter activity. The expression and secretion of IL-1β induced by EGF considerably reduced chemotherapeutic drug cisplatin-induced cell death. These results showed that EGF enhanced the expression of IL-1β, which was mediated by the Akt/NF-κB pathway. The activation of EGF signaling and increase of IL-1β contributed to chemotherapeutic resistance of cancer cells, suggesting that the expression of IL-1β may be used as a biomarker to evaluate successful cancer treatment.

Citation Format: Chi-Ruei Huang, Jhen-Hong Yang, Wen-Chang Chang, Ben-Kuen Chen. Epidermal growth factor protects squamous cell carcinoma against cisplatin-induced cytotoxicity through increased interleukin-1β expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 999. doi:10.1158/1538-7445.AM2013-999
Abstract ADV02: Black voices on health: Exploring possibilities for community-based research on cancer and co-morbidities amongst rural California Central Coast African Americans.
Authors: Austin-Schreher Carmelita
Published: August 2014

Carmelita Austin-Schreher, a breast cancer survivor who wanted to connect African-Americans to early detection education, support and services formed the African-American Community Health Group of the Central Coast with-in 4 months of her diagnosis. Beginning in 1998, we responded as a self-help group to the disproportionately high breast cancer mortality rates of African-American women, and the need for ethnically sensitive services. Carmelita and community members envisioned a group that would not only educate the African-American community about cancer, but one that would provide one-to-one and group support, a safe and comfortable environment for discussion, and would respect the cultural needs of our community. In order to provide its participants with the highest level of care and education, African-American Community Health Group is committed to staying on top of the latest news in health and cancer screening, treatment and research. African-American Community Health Group is proud of being a “grassroots” organization and is therefore dedicated to providing comprehensive screening outreach, health education, and long-term advocacy to empower all African-Americans in the central coast community.

We continue to provide crucial cancer education and prevention services as well as peer support for people with cancer through targeted projects. However, in addition to these activities we expanded health promotion and disease prevention activities of our organization to providing broad-based health education to the larger African-American and underserved communities including men and families, through office hours, library, support groups, seminars, peer and leadership training, and health fairs.

The mission of the African-American Community Health Group is to empower the African-American community of the central coast to be active and informed health consumers and survivors through self-help activities, advocacy training, and health education. Additionally, we work to create a dialogue with the community at large about racial disparities in health and the need for increased cultural and racial sensitivity.

Citation Format: Carmelita Austin-Schreher. Black voices on health: Exploring possibilities for community-based research on cancer and co-morbidities amongst rural California Central Coast African Americans. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr ADV02. doi:10.1158/1538-7445.AM2013-ADV02
Abstract ADV12: Banner Good Samaritan Medical Center's Oncology Program.
Authors: Jones Bonita
Published: August 2014

Banner Good Samaritan Medical Center in Phoenix, Arizona is the flagship medical center within Banner Health with over 650 beds. Our medical center has been consistently ranked as one of America's "Best Hospitals" by U.S. News & World Report.

Banner Good Samaritan Medical Center's mission statement: We exist to make a difference in the lives of the people we serve through excellent patient care.

Banner Good Samaritan's cancer program offer's state-of-the-art inpatient and outpatient services, advanced detection and treatments along with a wide range of support services for all types of cancer including breast cancer, lung cancer, head and neck cancers, leukemia and colorectal/pancreas/liver cancers.

Citation Format: Bonita Jones. Banner Good Samaritan Medical Center's Oncology Program. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr ADV12. doi:10.1158/1538-7445.AM2013-ADV12
Abstract ADV18: American indian screening initiatives: Gaining trust- reducing disparities.
Authors: Powell Kim
Published: August 2014

The Montana Affiliate of Susan G. Komen for the Cure® is dedicated to combating breast cancer at every front. Up to 75 percent of the Affiliate's net income goes toward funding grants to local hospitals and community organizations that provide breast health education and breast cancer screening and treatment programs for medically underserved women. The remaining income supports the national Komen Grants Programs, which funds groundbreaking breast cancer research, meritorious awards and educational and scientific programs around the world.

The Montana Affiliate of Susan G. Komen for the Cure serves the 4th largest geographic area in the country. American Indians living throughout Montana as members of seven distinct and independent tribal reservations, most in rural or “frontier” regions of the state. American Indian women in MT are more likely to live in poverty, be uninsured and face a higher risk of death from breast cancer due to late diagnosis.

To address this, Komen Montana has embarked on a comprehensive approach to address disparities and barriers that American Indian Women face in breast cancer screening. Since 2002, Komen Montana has funded screening mammography programs including funding mobile mammography clinics at PowWow events. Komen MT has partners with state as private agencies to identify traditional beliefs and Native cultural beliefs that serve as a deterrent to quality breast health programs. Most recently, a Komen Montana Community Grant, “Going Pink on the Red Road: has facilitated formation of a seven-tribe advisory council to draw upon the strengths of tribal representatives in the development of culturally specific resources and methods.

Komen Montana seeks to provide a significantly positive impact for American Indian women in the area of breast health by decreasing barriers, increasing culture-specific access and intervention, and decreasing the morbidity and mortality among Native women.

Citation Format: Kim Powell. American indian screening initiatives: Gaining trust- reducing disparities. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr ADV18. doi:10.1158/1538-7445.AM2013-ADV18
Abstract ADV20: For constructing an open society to cancer recognition.
Authors: Sakurai Naomi
Published: August 2014

Our mission: Getting a better understanding of cancer survivorship in Japan.

Our vision: Constructing an open society to cancer recognition.

HOPE Project started as a campaign of survivorship in Japan. We target cancer survivors including child cancer their and families. We have approximately 100 members.

Cancer patients face three kinds of problems; physical, emotional and social situations. In Japan, cancer survivors have to go through many misunderstandings and prejudices.

HOPE Project focuses on these issues and problems cancer survivors face that are difficult to solve in Japan.

Citation Format: Naomi Sakurai. For constructing an open society to cancer recognition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr ADV20. doi:10.1158/1538-7445.AM2013-ADV20
Abstract LB-112: Increase in glutaminase (GLS1) levels through SLUG-induced repression of hsa-miR-23a in triple negative breast cancer cells.
Authors: Mittal Mukul K. , Chaudhuri Gautam
Published: August 2014

Aggressive breast cancers of the triple negative type (TNBC) are often characterized by their high rate of proliferation and dissemination to other organs. One hallmark of this type of cancer cells is their adaptation to rely upon an altered metabolic scheme that includes changes in the glycolytic pathway, known as the Warburg effect, and elevated glutamine metabolism. Glutamine is taken up in a high rate by the proliferating cells and metabolized to provide a major source of energy and nitrogen for biosynthesis of nucleic acids. It is also used as a carbon substrate for anabolic processes in the cancer cells but the regulation of glutamine metabolism in the TNBC cells is not studied in details. Glutamine metabolism is thus implicated as a viable target for anticancer chemotherapy. Here we report that the transcriptional repressor protein SLUG, which is highly expressed in the most of the subtypes of the TNBC cells, indirectly up regulates the level of the glutaminase GLS1 through the repression of hsa-miR-23a gene. Knockdown of SLUG in the SLUG-high TNBC cells increases the hsa-miR-23a levels with subsequent decrease in the GLS1 levels. SLUG binds to the E2-box sequences at the hsa-miR-23a gene promoter and heterochromatinizes the promoter DNA through chromatin remodeling. A specific double-stranded DNA decoy against SLUG also alleviates the SLUG repression of the hsa-miR-23a gene promoter and thus decreases the glutaminase levels in the TNBC cells inhibiting the tumor cell growth. We postulate that maintenance of normal levels of GLS1 in the TNBC cells through the inhibition of the functions of SLUG will control aggressiveness and multiplication of breast tumors. Supported in parts by the DOD-CDMRP grants BC050641, BC086542 and BC103645 to GC.

Citation Format: Mukul K. Mittal, Gautam Chaudhuri. Increase in glutaminase (GLS1) levels through SLUG-induced repression of hsa-miR-23a in triple negative breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-112. doi:10.1158/1538-7445.AM2013-LB-112
Abstract LB-120: Large-scale cancer cell line screening with a novel and selective HDAC-6 inhibitor (ACY-1215) identifies candidate predictive biomarkers for breast cancer.
Authors: Yang Min , Tamang David , Jones Simon S. , Di Lie
Published: August 2014

ACY-1215 is a novel and selective inhibitor of HDAC6 currently in Phase 1 clinical trials in combination with bortezomib (Velcade) or lenalidomide (Revlimid) in relapsed/refractory multiple myeloma. Inhibitors of HDACs have demonstrated potent anti-cancer activity mediated by increased levels of acetylation of both histone and non-histone proteins, resulting in growth arrest, cell differentiation and apoptosis. In the present work, the broader anti-tumor activity of ACY-1215 was investigated with a panel of 65 human tumor cell lines derived from the major cancer types, to define additional oncology indications for clinical development and to identify candidate biomarkers of tumor sensitivity and drug resistance.

A group of 14 breast cancer cell lines was used to identify potential predictive biomarkers based on the wide range of sensitivity to ACY-1215 allowing robust correlation analysis. A panel of 42 genes was identified based on cellular sensitivity to ACY-1215 (IC50 values) correlating to gene expression levels and underlying genetic mutations in the individual cell lines as reported in the Cancer Cell Line Encyclopedia (CCLE). The Reactome “Functional Interaction Cytoscape Plugin” was used to partition these signatures genes into cancer-associated networks, which included the PIK3R2, ERBB2/STAT3, and TGFB3 signaling pathways. Association with these pathways and potential mechanism of action is consistent with observed synergistic anti-tumor activity between ACY-1215 and PI3K inhibitors. Also Gene Set Enrichment Analysis (GSEA), correlating ACY-1215 sensitivity with gene expression levels, revealed significant over-representation of genes in the p53 pathway, and pathways regulating cytoskeletal structure, cell adhesion, cell cycle and proliferation. A subset of these results support the proposed cytotoxic activity of selective HDAC6 inhibition through blocking of cell motility and misfolded protein clearance, while other findings suggest further novel pathways affected by inhibition of HDAC6.

Confirmation of predicted sensitive and resistant cell lines using the gene signatures will lead to the development of predictive biomarkers and selection of tumor type(s) for in vitro and in vivo validation with ACY-1215 in combination with novel and approved standard of care therapeutics.

Citation Format: Min Yang, David Tamang, Simon S. Jones, Lie Di. Large-scale cancer cell line screening with a novel and selective HDAC-6 inhibitor (ACY-1215) identifies candidate predictive biomarkers for breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-120. doi:10.1158/1538-7445.AM2013-LB-120
Abstract LB-125: A novel telomerase inhibitor.
Authors: Mender Ilgen , Gryaznov Sergei , Dikmen Zeliha Gunnur , Wright Woodring , Shay Jerry
Published: August 2014

Telomeres are highly specialized structures that are found at the very ends of linear chromosomes. Normal human somatic cells progressively lose their telomeres with each cell division due to the end replication problem. Unlike most normal somatic cells, the vast majority of advanced cancers have telomerase activity, which overcomes the end replication problem by adding multiple TTAGGG sequences to the end of linear chromosomes. Because of the selective expression of this enzyme in cancer cells, it is an almost universal target for antitumor drug development. However, there are surprisingly few telomerase inhibitors in clinical trials. We have modified a chemotherapeutic antimetabolite agent, 6-thioguanine (6-thio-G) so that this newly synthesized compound targets telomeres while retaining its antimetabolite activity. 6-thio-dG is a nucleoside analogue that is recognized by telomerase and is incorporated into telomeres. Telomeric incorporation results in structurally modified telomeres, functionally uncapping the shelterin protective complex, resulting in telomere associated DNA damage foci. Here, we report that 6-thio-dG causes progressive telomere shortening independent from inhibition of telomerase activity and induces telomere dysfunction in HCT116 human colon cancer cell line. Combination of the telomerase inhibitor GRN163L, which is in advanced clinical trials, and 6-thio-dG have additive effects on telomere shortening in HCT116 cells. 6-thio-dG treatment altered HCT116 cellular morphology and killed most of these cells within 1 week. Normal BJ fibroblast cells, which are telomerase silent, were not affected by 6-thio-dG in either cell morphology after 1 week or in enhanced telomere shortening after long-term treatment. These results show that 6-thio-dG is a novel anti-cancer inhibitor and a potential therapeutic agent targeting both telomeres and general DNA damage.

Citation Format: Ilgen Mender, Sergei Gryaznov, Zeliha Gunnur Dikmen, Woodring Wright, Jerry Shay. A novel telomerase inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-125. doi:10.1158/1538-7445.AM2013-LB-125
Abstract LB-136: Creation of androgen independent prostate cancer cell lines using targeting nucleases.
Authors: Nyquist Michael D. , Li Yingming , Dehm Scott M.
Published: August 2014

Understanding mechanisms by which advanced prostate cancer (PCa) progresses to a castration resistant PCa (CRPC) phenotype is crucial for tailoring targeted therapies for individual patients. Constitutively active androgen receptor (AR) splice variants that lack the ligand binding domain drive androgen independent growth in cell lines and xenograft models of PCa and their overexpression in CRPC metastases is associated with poor prognosis. However, the mechanism of AR splice variant overexpression in CRPC is not completely understood. We have shown that diverse genomic rearrangements within the AR gene are linked to AR splicing alterations in PCa cell lines, xenografts, and CRPC metastases. To test whether these AR gene rearrangements drive AR splice variant synthesis and a CRPC phenotype, we developed transcription activator-like effector nucleases (TALENs) for precision genome engineering in androgen-sensitive PCa cells. Engineering of specific AR gene rearrangements induced splicing alterations and efficient expression of AR splice variants. Functionally, these genome-engineered cells displayed constitutive, ligand-independent AR transcriptional activity and an androgen-independent growth profile. These fundamental properties of CRPC were blocked following siRNA-mediated knock-down of truncated AR variants. Overall, these data demonstrate that AR gene rearrangements induce fundamental aspects of the CRPC phenotype including constitutive, ligand-independent, AR splice variant activity. Overall, these data advance the concept of AR splice variants as key drivers of advanced disease, and provide new genome-engineered models that could be used to develop agents targeted to these AR-derived species.

Citation Format: Michael D. Nyquist, Yingming Li, Scott M. Dehm. Creation of androgen independent prostate cancer cell lines using targeting nucleases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-136. doi:10.1158/1538-7445.AM2013-LB-136
Abstract LB-15: Frequency of aspirin use and prostate cancer mortality among prostate cancer cases in the control arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
Authors: Daugherty Sarah E. , Pfeiffer Ruth , Ghazarian Armen , Izmirlian Grant , Prorok Phil , McGlynn Katherine
Published: August 2014

Background: Aspirin may slow progression of cancer through the inhibition of platelet aggregation as experimental research has shown that platelets play a role in cancer cell dissemination and metastatic growth. While a 10% reduction in prostate cancer risk has been associated with regular aspirin use, only a few epidemiological studies have evaluated the association between aspirin use and prostate cancer mortality among prostate cancer cases.

Methods: Participants included 3857 men, age 55-74, who were diagnosed with prostate cancer in the control arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial between 1993-2009. The frequency of aspirin use one year prior to baseline (1993-2001) was ascertained through a self-administered questionnaire. Death due to prostate cancer was ascertained by annual questionnaire and linkage to the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using COX proportional hazards models using age as the time metric and adjusting for clinical stage, Gleason score, primary treatment, smoking status, body mass index, race, history of heart attack, and history of stroke.

Results: After a median of 5 years of follow-up, 136 cases died of prostate cancer. No significant association with prostate cancer mortality was observed between cases who reported pre-diagnostic daily or more than daily aspirin use compared to cases who reported no aspirin use (HR=0.77; 95% CI 0.48-1.25). Among those diagnosed with clinically advanced stage (III, IV) disease, an inverse association with prostate cancer mortality was observed for cases who reported daily or more than daily aspirin use (HR=0.37; 95% CI 0.15-0.92), while no association for daily or more than daily users was seen among those with clinically localized prostate cancer (HR=0.86; 95% CI 0.47-1.58).

Conclusion: Pre-diagnostic use of aspirin was not significantly associated with prostate cancer mortality based on cases diagnosed in the PLCO control arm, although a reduction in risk of prostate cancer mortality was observed among those with advanced stage disease in a subgroup analysis.

Citation Format: Sarah E. Daugherty, Ruth Pfeiffer, Armen Ghazarian, Grant Izmirlian, Phil Prorok, Katherine McGlynn. Frequency of aspirin use and prostate cancer mortality among prostate cancer cases in the control arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-15. doi:10.1158/1538-7445.AM2013-LB-15
Abstract LB-150: Carcinogenic Helicobacter pylori infection induces base excision repair intermediates to trigger homologous-dependent repair in human gastric epithelial cells.
Authors: Kidane Dawit , Murphy Drew L , Sweasy Joann.B
Published: August 2014

Helicobacter pylori infection of the human stomach is associated with disease-causing inflammation that elicits DNA damage in both bacterial and host cells. To investigate base excision repair (BER) as the first line of defense against bacterial infection to maintain host cell genomic stability, we examined H. pylori induced BER intermediates that could be responsible for double strand break (DSB) and homologous dependent repair (HDR). Here, we show that H. pylori infection significantly increases abasic sites (AP) that are not repaired by BER. As a result, unrepaired BER intermediates lead to slow replication fork speed and replication fork collapse that eventually is converted to double strand breaks. To determine if H. pylori infection enhances recombinational repair to process DSBs, we have analyzed the cells for homologous directed repair pathways. Direct measurement of HDR using a GFP-based assay demonstrates significantly increased HDR in cells infected with H. pylori. Our data suggest that H. pylori induced BER intermediates are required to activate homologous directed repair pathways. Therefore, our finding suggests that BER is the first line of defense against H. pylori induced DNA damage followed by HDR, to maintain genomic integrity of gastric cells.

Citation Format: Dawit Kidane, Drew L Murphy, Joann.B Sweasy. Carcinogenic Helicobacter pylori infection induces base excision repair intermediates to trigger homologous-dependent repair in human gastric epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-150. doi:10.1158/1538-7445.AM2013-LB-150
Abstract LB-151: REV1 has critical roles in base excision repair intermediate-mediated transversion mutations but not for O6-methylguanine-initiated mutations in vertebrate cells.
Authors: Nakamura Jun , Tian Xu , Swenberg James
Published: August 2014

Isogenic chicken DT40 cells deficient in various DNA repair pathways are a great tool for understanding the DNA damage response and mutagenesis caused by genotoxic agents by a comparison of mutants and parental DT40 cells. We recently found that ~55% of PIGO mutations are located at A:T sites with a high frequency of A to T transversion mutations in DT40 cells exposed to methyl methanesulfonate (MMS). These results suggest that A to T transversion mutations found in MMS exposure-derived PIGO mutant cells are due to base excision repair intermediates, such as abasic sites and single strand breaks originated from N3-methyladenine. It has been reported that DNA repair protein REV1 acts as not only as a deoxycytidine transferase across abasic sites but also as a scaffold protein to coordinate translesion DNA synthesis (TLS) polymerase switching. To address effects of REV1 on MMS-induced PIGO mutations in DT40 cells, we exposed REV1 knockout DT40 cells to low-dose MMS. REV1 knockout DT40 cells showed hyper-sensitivity in cell survival after MMS treatment with no increase in PIG-O mutations. These results indicate that PIG-O mutations in DT40 cells exposed to MMS are caused through REV1-dependent, but REV1 deoxycytidyl transferase-independent, TLS. In contrast to MMS, REV1 and parental DT40 cells showed similar toxicity and mutagenicity caused by a combination of low-dose N-methyl-N-nitrosourea and O6-benzylguanine. These results suggest that base excision repair intermediates appear to initiate REV1-dependent TLS, whereas, O6-methylguanine could be by-passed by replicative polymerases, such as polymerase delta complexes, with an associated increase in G to A transition mutations.

Citation Format: Jun Nakamura, Xu Tian, James Swenberg. REV1 has critical roles in base excision repair intermediate-mediated transversion mutations but not for O6-methylguanine-initiated mutations in vertebrate cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-151. doi:10.1158/1538-7445.AM2013-LB-151