bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 612: Endostatin is a novel inhibitor of androgen receptor function in prostate cancer
Authors: Lee Joo Hyoung , Isayeva Tatyana , Larson Matthew , Chanda Diptiman , Chesnokov Igor , Ponnazhagan Selvarangan 
Published: May 2015

Abstract
Abnormalities in androgen-androgen receptor (AR) axis have long been recognized for their roles in promoting prostate tumor growth and metastasis. Conventional therapies targeting androgen ablation show transient tumor regression, however, when the tumor recurs during castration-refractory metastatic stage, the current treatment options are very limited. Although the precise mechanism by which prostate cancer (PCa) cells circumvent the androgen deprivation is unclear, recurring tumors have been shown to retain AR activity and upregulation of AR-target gene expression such as prostate specific antigen (PSA), suggesting that targeting AR remains a key component of developing novel therapeutic strategies. Here, we show a profound effect of endostatin, an endogenous angiogenesis inhibitor, on proliferation and invasion of AR-positive PCa cells by targeting AR function. The present study identified that intracellular trafficking of endostatin and direct interaction with AR disrupts AR nuclear translocation and the consequent transcriptional activation of PSA gene. In addition, our structural modeling and site-directed mutagenesis studies suggest that the binding mechanism may include the interaction of bulky side chains (F31 and F34) present in endostatin with the co-activator binding interface (AF-2) in AR ligand-binding domain (LBD). Regarding drug resistance to the second-generation androgen antagonists in patients with metastatic PCa, recent studies revealed that a missense mutation in AR LBD (F876L) and the consequential antagonist-to-agonist switch confers continued AR activity. In this context, our study suggests that endostatin can be recognized as an endogenous AR inhibitor where its molecular interaction with AR may prevent from agonistic switch of AR function by fully masking the AF-2 subdomain. Overall, the current finding provides new insights into endostatin whose anti-cancer activity is not only limited to inhibiting angiogenesis, but can also be expanded to suppressing AR-mediated PCa progression by disrupting AR transactivation.
Citation Format: Joo Hyoung Lee, Tatyana Isayeva, Matthew Larson, Diptiman Chanda, Igor Chesnokov, Selvarangan Ponnazhagan. Endostatin is a novel inhibitor of androgen receptor function in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 612. doi:10.1158/1538-7445.AM2014-612
Abstract 615: TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells
Authors: Asuthkar Swapna , Velpula Kiran , Zakharian Eleonora 
Published: May 2015

Abstract
TRPM8 channels are highly expressed in prostate cancer cells but the physiological and pathological functions of TRPM8 in these cells are not known. In addition to prostate cancer (PC) cells, TRPM8 is expressed in sensory neurons where it acts as a sensor of cold. Recently, trpm8 has been identified as both an important gene regulated by androgens and a critical regulator of Ca2+ homeostasis. The androgen and its receptor (AR) are pivotal in the biology of sex hormone-regulated malignancies, with PC the most affected tumor. From the chromatin-immunoprecipitation (ChIP) analysis, we observed that an androgen response element (ARE) mediates androgen regulation of TRPM8. Further, using immunoprecipitation and calcium-imaging experiments, we identified that TRPM8 Ca+2 channels are functionally associated with androgens (testosterone and 5α-dihydrotestosterone) in the prostate. We also identified that unlike prostate cancer cell lines (LNCAP, PC3 and RWPE2) and normal prostate tissues, prostate tumor tissues (grade 1-4) showed high levels of TRPM8 which was predominantly localized as the plasma membrane protein at the tumor periphery. Of note, the decreased stabilization of TRPM8 on the plasma membrane was associated with increased expression of AR protein. These results suggest an important role of androgen signaling in trpm8 gene transcription corroborating to cancer progression and clinical lethality in prostate cancer.
Citation Format: Swapna Asuthkar, Kiran Velpula, Eleonora Zakharian. TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 615. doi:10.1158/1538-7445.AM2014-615
Abstract 617: Repression of cell proliferation and androgen receptor activity by 2’-hydroxyflavanone in prostate cancer cells
Authors: Mizokami Atsushi , Ofude Mitsuo , Kumaki Misako , Izumi Kouji , Konaka Hiroyuki , Kadono Yoshifumi , Shin Minkyoung , Zhang Jian , Keller Evan T. , Namiki Mikio 
Published: May 2015

Abstract
Background: Since androgen-androgen receptor (AR) axis is the main stream for development and progression of prostate cancer, androgen-deprivation therapy (ADT) is conducted as a first line hormonal therapy using medical castration, such as LH-RH agonists, LH-RH antagonist, and antiandrogen for advanced PCa. After an initial response to ADT, however, PCa eventually loses responsiveness to ADT and progresses into castration-resistant prostate cancer (CRPC). Prevention of the development of castration-resistant from hormone-naïve prostate cancer is an important issue in maintaining the quality of life of the patients. We explored the effect of 2’-hydroxyflavanone on proliferation and androgen responsiveness using prostate cancer cell lines.
Materials and Methods: To investigate the effect of 2’ -hydroxyflavanone on proliferation, prostate cancer cells were treated with 2’-hydroxyflavanone. Androgen-responsiveness in LNCaP cells was confirmed by luciferase assay after transfection of luciferase reporter driven by prostate specific antigen promoter. To detect androgen receptor (AR) expression, reverse transcriptase polymerase chain reaction and western blot analysis were conducted.
Results: 2’ -Hydroxyflavanone inhibited the proliferation of PC-3 and DU145 cells by induction of apoptosis. 2’ -Hydroxyflavanone inhibited the proliferation of LNCaP cells stimulated by androgens and attenuated androgen-responsiveness through down-regulation of AR protein.
Conclusion: 2’ -Hydroxyflavanone not only inhibited proliferation of prostate cancer cells, but also repressed androgen-responsiveness, suggesting that it might be an useful agent in preventing recurrence of prostate cancer.
Citation Format: Atsushi Mizokami, Mitsuo Ofude, Misako Kumaki, Kouji Izumi, Hiroyuki Konaka, Yoshifumi Kadono, Minkyoung Shin, Jian Zhang, Evan T. Keller, Mikio Namiki. Repression of cell proliferation and androgen receptor activity by 2’-hydroxyflavanone in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 617. doi:10.1158/1538-7445.AM2014-617
Abstract 620: Evidence for combination tamoxifen and betulinic acid to treat hormone responsive- and unresponsive breast cancer by attenuation of Pygopus expression
Authors: Tzenov Youlian , Andrews Philip , Popadiuk Cathy , Kao Kenneth R. 
Published: May 2015

Abstract
The presence of the estrogen and progesterone hormone receptors (ER and PR) in advanced breast cancer tumour nuclei is predictive for response to hormone disruptive therapy. However, the accuracy of ER and PR testing can be variable and although patients receive significant benefit from hormone therapy, they ultimately become refractory to treatment. The chromatin remodeling protein: human Pygopus2 (hPygo2), is important for oncogenic growth and cell cycle progression and may serve as a diagnostic or targetable biomarker for breast cancer. Here we demonstrate that ER-alpha (Erα)−Sp1 transcription factor (Sp1) complexes associate with chromatin at adjacent motifs within the hPygo2 promoter in both hormone receptor positive and negative breast cancer cells. Erα agonists induced, while antagonists inhibited hPygo2 mRNA and protein expression. Erα and Sp1 occupancy at the hPygo2 promoter required intact promoter binding sites and functional DNA binding domains. Estrogen (E2) increased, while Fulvestrant decreased, Erα binding to the hPygo2 promoter with no effect on Sp1. Furthermore, Sp1-directed siRNA reduced Sp1 occupancy at the hPygo2 promoter and decreased hPygo2 mRNA and protein expression in both Erα-expressing (+) and Erα-nonexpressing (-) cells. Betulinic acid, an Sp1 inhibitor, caused cell cycle arrest, reduced Sp1 binding to the hPygo2 promoter and reduced hPygo2 expression in Erα- cell lines. The activation of hPygo2 expression either cooperatively or independently by Erα and Sp1 suggests their potential diagnostic and therapeutic benefit for both hormone responsive and unresponsive breast cancer.
Citation Format: Youlian Tzenov, Philip Andrews, Cathy Popadiuk, Kenneth R. Kao. Evidence for combination tamoxifen and betulinic acid to treat hormone responsive- and unresponsive breast cancer by attenuation of Pygopus expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 620. doi:10.1158/1538-7445.AM2014-620
Abstract 622: S-equol, an estrogen receptor β agonist, inhibits tumor growth and progression of breast cancer
Authors: Samayoa Cathy , Krishnegowda Naveen K. , Krishnan Samaya R. , Vadlamudi Ratna K. , Tekmal Rajeshwar R. 
Published: May 2015

Abstract
Breast cancer is the primary cause of cancer-associated mortality in women worldwide. Estrogen and the Estrogen Receptors (ER) play a significant role in breast cancer, with over two-thirds of breast cancers expressing ERα. Current endocrine therapy, such as aromatase inhibitors, target estrogen biosynthesis and anti-estrogens target ERα. However, therapeutic resistance frequently arises. In addition to the importance of ERα, ERβ has also been shown to play a critical, but opposing role in breast cancer. ERβ has been shown to inhibit the growth of ERα-positive breast cancer cells. The ratio of ERα to ERβ, in addition to the cross talk between ER's and growth factor signaling, has been implicated in the development of therapeutic resistance. Recently, several plant-derived compounds that exhibit ERβ agonist activity have been identified. S-equol is a potent ERβ agonist and a metabolite from the soy isoflavone daidzein, and has been previously shown to alleviate menopausal symptoms in a clinical trial. Activation of ERβ, or its over expression, shifts the balance of ER's from the oncogenic action of ERα to the tumor suppressor activity of ERβ, and therefore may be a valuable therapeutic approach in the treatment of breast cancer. In this study we sought out to determine the efficacy of the ERβ agonist, S-equol, in inhibiting the growth and progression of breast tumors using a syngeneic mouse model. We used mouse mammary tumor cells expressing endogenous ERβ, and to determine the contribution of ERβ, cells with knockdown of ERβ were generated using shRNA. ERβ mRNA and protein expression was analyzed using qRT-PCR and western blot respectively. Syngeneic tumors were established and mice were treated with either a vehicle control or S-equol. Treatment with S-equol reduces tumor volume and inhibits the progression of mouse mammary tumor cells in tumors expressing ERβ. Our mechanistic studies show that S-equol reduces the expression of ERα, and increases the expression of p53 and p27 in an ERβ dependent manner. Additionally, S-equol modulates the expression of inflammatory molecules involved in aromatase expression and promotes the differentiation of cancer stem cells. In conclusion, this study suggests that targeting ERβ may be a valuable strategy in treatment of breast cancer.
Citation Format: Cathy Samayoa, Naveen K. Krishnegowda, Samaya R. Krishnan, Ratna K. Vadlamudi, Rajeshwar R. Tekmal. S-equol, an estrogen receptor β agonist, inhibits tumor growth and progression of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 622. doi:10.1158/1538-7445.AM2014-622
Abstract 628: Pan-Bcl-2 inhibitor, GX15-070 (Obatoclax), decreases human T regulatory lymphocytes while preserving effector T Lymphocytes: A rationale for its use in combination immunotherapy
Authors: Kim Peter S. , Jochems Caroline , Grenga Italia , Donahue Renee N. , Tsang Kwong Y. , Gulley James L. , Schlom Jeffrey , Farsaci Benedetto 
Published: May 2015

Abstract
Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T-cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T-cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly down-regulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8+:Treg and CD4+:Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8+ T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor.
Citation Format: Peter S. Kim, Caroline Jochems, Italia Grenga, Renee N. Donahue, Kwong Y. Tsang, James L. Gulley, Jeffrey Schlom, Benedetto Farsaci. Pan-Bcl-2 inhibitor, GX15-070 (Obatoclax), decreases human T regulatory lymphocytes while preserving effector T Lymphocytes: A rationale for its use in combination immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 628. doi:10.1158/1538-7445.AM2014-628
Abstract 632: Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing
Authors: Gameiro Sofia R. , Jammeh Momodou L. , Wattenberg Max M. , Tsang Kwong Y. , Ferrone Soldano , Hodge James W. 
Published: May 2015

Abstract
Radiation therapy (RT) is used for local tumor control through direct killing of tumor cells. Radiation-induced cell death can trigger tumor antigen-specific immune responses, but these are often noncurative. Radiation has been demonstrated to induce immunogenic modulation (IM) in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell-mediated killing. Little is known about the mechanism(s) underlying IM elicited by sub-lethal radiation dosing. We have examined the molecular and immunogenic consequences of radiation exposure in breast, lung, and prostate human carcinoma cells. Radiation induced secretion of ATP and HMGB1 in both dying and surviving tumor cells. In vitro and in vivo tumor irradiation induced significant upregulation of multiple components of the antigen-processing machinery and calreticulin cell-surface expression. Augmented CTL lysis specific for several tumor-associated antigens was largely dictated by the presence of calreticulin on the surface of tumor cells and constituted an adaptive response to endoplasmic reticulum stress, mediated by activation of the unfolded protein response.
This study provides evidence that radiation induces a continuum of immunogenic alterations in tumor biology, from immunogenic modulation to immunogenic cell death. We also expand the concept of immunogenic modulation, where surviving tumor cells recovering from radiation-induced endoplasmic reticulum stress become more sensitive to CTL killing. These observations offer a rationale for the combined use of radiation with immunotherapy, including for patients failing RT alone.
Citation Format: Sofia R. Gameiro, Momodou L. Jammeh, Max M. Wattenberg, Kwong Y. Tsang, Soldano Ferrone, James W. Hodge. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 632. doi:10.1158/1538-7445.AM2014-632
Abstract 634: Combination chemotherapy significantly reduces indoleamine 2,3-dioxygenase activity in NSCLC patients
Authors: Schafer Cara C. , Wang Yong , Sawant Anandi , Jin Tong Huan , Ponnazhagan Selvarangan , Grant Stefan C. , Deshane Jessy S. 
Published: May 2015

Abstract
Heterogeneity and immunosuppression in the tumor microenvironment (TME) has dampened the efficacy of current frontline combination chemotherapies for lung cancer which has provided limited improvement in patient survival. Modified amino acid metabolism in the TME contributes to lung cancer progression and suppression of anti-tumor immunity. Enhanced tryptophan metabolism in primary lung cancer patients is indicative of advanced disease stage. One of the key regulators of tryptophan metabolism is an intracellular, heme-containing enzyme indoleamine 2,3-dioxygenase (IDO). IDO catabolizes the breakdown of tryptophan into a toxic, immunosuppressive metabolite, L-Kynurenine (L-Kyn). Induction of IDO and accumulation of its metabolite correlates with poor prognosis and overall patient survival.
We hypothesized that IDO enzymatic activity would be elevated in lung cancer patients compared to normal healthy controls. We predicted that combination chemotherapy strategies would modulate serum levels of L-Kyn and IDO activity in the immune compartment of lung cancer patients. Using an IDO enzymatic activity assay to measure the production of L-Kyn, we demonstrate that prior to receiving combination chemotherapies, Non-Small Cell Lung Cancer (NSCLC) patients (n=11) display significantly elevated levels of this immunosuppressive serum metabolite compared to healthy relatives (n=8) (Student's t-test p=0.000087; Paired Means p=0.0001). Following the second cycle of treatment, serum L-Kyn was reduced significantly (Student's t-test p=0.023; Paired Means p=0.043) in a subset of patients (n=3 of 5) suggesting response to chemotherapy, but these post-treatment levels remained elevated overall compared to healthy relatives. Additionally, greater levels of IDO enzymatic activity were observed in circulating immunosuppressive myeloid-derived suppressor cells from NSCLC patients and peripheral blood mononuclear cells prior to receiving combination chemotherapy compared to those from healthy relatives.
These preliminary studies suggest that the IDO enzymatic pathway and tryptophan metabolism may serve as important therapeutic targets and diagnostic markers in predicting clinical outcomes of combination chemotherapies in the treatment of NSCLC in humans.
Citation Format: Cara C. Schafer, Yong Wang, Anandi Sawant, Tong Huan Jin, Selvarangan Ponnazhagan, Stefan C. Grant, Jessy S. Deshane. Combination chemotherapy significantly reduces indoleamine 2,3-dioxygenase activity in NSCLC patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 634. doi:10.1158/1538-7445.AM2014-634
Abstract 637: Chemotherapy enhances recombinant lipoimmunogen-based antitumor immunity against cervical cancer
Authors: Liu Shih-Jen , Chang Li-Sheng , Yeh Yi-Chen , Leng Chih-Hsiang 
Published: May 2015

Abstract
Although CTLs play a major role in eradicating cancer cells during immunotherapy, the development of immune escape often limits the success of such therapy. Therefore, the simultaneous induction of CTLs against cancer and administration of chemotherapy would be feasible to overcome the limitation. The recombinant lipoprotein consisting of inactive E7 (E7m) biologically linked to a bacterial lipid moiety (rlipo-E7m) induces the maturation of mouse bone marrow-derived dendritic cells through toll-like receptor 2 (TLR2), E7-specific cytotoxic T lymphocytes (CTLs) responses and inhibits tumor growth. The large tumor (&gt; 10 mm diameter) was regressed when treated with rlipo-E7m and TLR9 agonist (oligodeoxynucleotide, CpG ODN). In addition, the combinations inhibit local immunosuppressive cells number (MDSCs, TAM and Tregs) and increase CTLs number in tumor infiltration. However, the tumor grew again at ∼ 50 days after tumor implantation. To improve the therapeutic effects of rlipo-E7m/CpG, cisplatin or gemcitabine was combined to treat large tumor. We found that the combinations increase the survival time of the tumor-bearing mice. The promising approach may be applied to other tumor antigen for other cancer immunotherapy.
Citation Format: Shih-Jen Liu, Li-Sheng Chang, Yi-Chen Yeh, Chih-Hsiang Leng. Chemotherapy enhances recombinant lipoimmunogen-based antitumor immunity against cervical cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2014-637