bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B57: The success of the Black and Blues Brunch
Authors: Jackson Kim Hall
Published: October 2015

KHJ Enterprise, LLC presents:

The Black & Blues Brunch @ Warmdaddy's Restaurant

An event to increase awareness and screening for colorectal cancer in the African American community. The black represents African American and the blue(s) is for the color associated with colorectal cancer.

The purpose of this project is to increase awareness about the critical need for colorectal screening in the African American community, in addition to understanding what early detection, diagnosis, and treatment options are available. The hope is that by providing critical information in a nontraditional, relaxed, “edu-tainment” setting more Philadelphians of African American descent will leave equipped with information to improve their health outcomes and the willingness and commitment to participate in a life-saving cancer screening

Citation Format: Kim Hall Jackson. The success of the Black and Blues Brunch. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B57.
Abstract B83: Predictors of cervical cancer screening among women receiving care in a safety-net health system
Authors: Ogunwale Abayomi N. , Sangi-Haghpeykar Haleh , Montealegre Jane , Nosek Margaret A. , Jibaja-Weiss Maria , Anderson Matthew L.
Published: October 2015

Objective: To identify factors impacting rates of cervical cancer screening among women receiving medical care through a safety-net health system.

Methods: A self-administered questionnaire was used to assess knowledge regarding cervical cancer, as well as individual attitudes, beliefs and perceptions among women presenting to two publically-funded community clinics. Sample size was powered to detect a 15% difference in screening prevalence (p <0.05).

Results: Of 1,094 women invited to participate, 983 subjects completed a questionnaire. Eighty two percent of subjects reported having had a Pap test in the past 3 years. Hispanic ethnicity and being born outside the U.S. were significantly associated with the lowest rates of screening, while African-American women had the highest screening rates. The majority of respondents had accurate knowledge regarding the Pap test and its role in cervical cancer screening. In addition to knowledge of the Pap test, we found that knowledge of cervical cancer risk factors, continuity of care and a sense of fatalism were each associated with higher rates of cervical cancer screening. We also found that a partner's opinion regarding the importance of testing was robustly associated with screening in Hispanic women (OR=10.7 p<0.0001). Low rates of screening among African-American and Caucasian women correlated with perceptions of poor provider communication, less social support and having multiple sexual partners.

Conclusions: In the absence of health access barriers, multiple socio-cultural factors significantly impact cervical cancer screening rates. Among Hispanic women, perceived attitudes of partners is strongly associated with participation in cervical cancer screening.

Citation Format: Abayomi N. Ogunwale, Haleh Sangi-Haghpeykar, Jane Montealegre, Margaret A. Nosek, Maria Jibaja-Weiss, Matthew L. Anderson. Predictors of cervical cancer screening among women receiving care in a safety-net health system. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B83.
Abstract IA07: In search of racial disparities in HPV vaccination
Authors: Brewer Noel T. , Moss Jennifer L. , Reiter Paul L.
Published: October 2015

Background: Racial disparities in cervical cancer deaths are longstanding, with African American and Latina women more likely to die from the disease. The advent of HPV vaccine created an opportunity to reduce or end these disparities, but only if uptake was either uniformly high across all females or higher among minority than non-minority females. Thus, interest in racial disparities in HPV vaccine coverage has been understandably high.

Findings: Data from several sources show racial disparities and “reverse disparities” in HPV vaccination coverage. First, the most reliable national data are from the National Immunization Survey Teen, a national survey of parents of adolescents with vaccination doses confirmed by physician records. NIS-Teen data show, depending on the year, higher initiation among Black and Latina teen girls. HPV vaccine completion rates in some years have been lower among these groups. Second, several large studies of insured women have shown lower rates of HPV vaccine initiation among Black women. Finally, many national surveys using self-reported data have shown no reliable pattern with respect to disparities in HPV vaccine initiation.

Another source of data is ecological analyses, comparing HPV vaccine coverage in states with lower and higher proportions of minority women. These analyses by Moss, Reiter and Brewer show that states with more African American residents had lower rates of HPV vaccine initiation among adolescent girls. However, we saw no disparities for completion or for proportion of Latina women.

A last source of data are studies of awareness, knowledge, beliefs and attitudes. These studies show a more regular pattern of lower awareness of and lower knowledge related to HPV vaccine among minority women compared to non-minority women. However, racial disparities are not universal across studies and not routinely present for other outcomes.

Commentary: Despite our best efforts to find racial disparities in HPV vaccination coverage, data from various sources suggest no clear pattern of ethnic or racial disparities for outcomes other than 3-dose series completion. Future studies should emphasize HPV vaccine initiation, which likely has a larger public health impact than series completion.

Citation Format: Noel T. Brewer, Jennifer L. Moss, Paul L. Reiter. In search of racial disparities in HPV vaccination. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA07.
Abstract IA15: FDA Center for Tobacco Products: Overview and research relevant to tobacco-related cancer and health disparities
Authors: Hoffman Allison C.
Published: October 2015

The U.S. Food and Drug Administration (FDA) Center for Tobacco Products (CTP) oversees the implementation of the Family Smoking Prevention and Tobacco Control Act (TCA). The Agency's responsibilities under the law include setting product standards for tobacco products, reviewing premarket applications for new and modified risk tobacco products, requiring new health warnings, and establishing and enforcing product advertising and promotion restrictions. The CTP Office of Science was established to ensure that a sound science exists with which to develop and assess the impact of the FDA's tobacco-related regulatory actions. This presentation will provide an overview of CTP, tobacco regulation, and research priorities, including research and activities that include cancer and health disparities outcomes.

Citation Format: Allison C. Hoffman. FDA Center for Tobacco Products: Overview and research relevant to tobacco-related cancer and health disparities. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA15.
Abstract A06: Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness
Authors: Lee Hyeon Jeong , Yue Shuhua , Li Junjie , Lee Seung-Young , Shao Tian , Song Bing , Cheng Liang , Masterson Timothy A. , Liu Xiaoqi , Ratliff Timothy L. , Cheng Ji-Xin
Published: October 2015

Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single-cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism.

Citation Format: Hyeon Jeong Lee, Shuhua Yue, Junjie Li, Seung-Young Lee, Tian Shao, Bing Song, Liang Cheng, Timothy A. Masterson, Xiaoqi Liu, Timothy L. Ratliff, Ji-Xin Cheng. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A06.
Abstract A15: Dual inhibition of the PI3K-mTOR signaling in combination with HER2 inhibitor is necessary for maximal antitumor activity in HER2+ breast cancer cells
Authors: De Pradip , Sun Yuliang , Carlson Jennifer , Friedman Lori , Dey Nandini , Leyland-Jones Brian
Published: October 2015

Background: Despite huge success in the treatment of HER2 amplified/overexpressed breast cancers, resistance is challenging problem even to combinations of HER2 targeting inhibitors. Multiple mechanisms of resistance have been studied and the PI3K-mTOR pathway inhibition is critical for the efficacy of HER2 inhibitors. Activating mutations in PIK3CA can overlap with HER2 overexpression and have been shown to confer resistance to HER2 inhibitors including trastuzumab (T) in preclinical studies.

Methods: HER2+/T-sensitive/PIK3CA wild type (BT474) and HER2+/PIK3CA mutated (HCC1954) cells were used for this study. The impact of PIK3CA mutation on the effect of HER2 and dual PI3K/mTOR inhibitors was assayed by immunoblot, proliferation and apoptosis assays. PI3K signaling was examined by immunoblot for phosphoproteins in the HER2-PI3K-mTOR signaling cascade. The combination of dual PI3K/mTOR inhibitor (GDC-0980) with HER2 antibodies (T or T-DM1) was studied in HER2 amplified models with wild type or mutant PIK3CA.

Results: Our data showed that 1) PIK3CA mutation in HER2+ cells was responsible for resistance to the HER2-specific antibody trastuzumab, 2) T-resistance conferred by this activating PIK3CA mutation was overcome by blockade of the PI3K-mTOR pathway with GDC-0980, 3) T-DM1 and GDC-0980 combination treatment greatly induced apoptosis of both BT474 and HCC1954 cells as indicated by Annexin V staining, 4) in mice bearing HER2+/T-sensitive/PIK3CA wild type xenografts (BT474), T or T-DM1 blocked tumor growth. The addition of a dual PI3K/mTOR inhibitor more significantly blocked tumor growth when compared to control group, 5) in a HER2+/PIK3CA mutant xenograft (HCC1954), dual PI3K/mTOR inhibition with GDC-0980 in combination with T or T-DM1 was required for blocked of tumor growth and tumor regression, and 6) immununo-staining of tumors from GDC-0980 treated mice showed growth inhibition (Ki67), and a decreased in associated angiogenesis (CD31).

Conclusion: These results suggest that the combination of GDC-0980 may be a potential strategy for the treatment of trastzumab-resistant breast cancer mediated by activating mutation of PIK3CA and this combination also provides benefit to HER2+/PIK3CA wild type tumors.

Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones. Dual inhibition of the PI3K-mTOR signaling in combination with HER2 inhibitor is necessary for maximal antitumor activity in HER2+ breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A15.
Abstract A16: DDR-mediated antitumor actions of PARP inhibitor: Can PI3K-mTOR pathway inhibitor be combined with PARP inhibitor in TNBT?
Authors: Dey Nandini , Carlson Jennifer H. , Sun Yuliang , Friedman Lori S. , De Pradip , Leyland-Jones Brian
Published: October 2015

Background: The PI3K pathway is known to contribute to DNA-damage repair (DDR). Recently we have reported that GDC-0980 a dual PI3K-mTOR inhibitor enhanced DNA-damage in triple negative breast cancer cells (De et al., Neoplasia, 2014). We utilized a mechanism-based approach to demonstrate that inhibition of DDR is another mode of action for GDC-0980. Here we hypothesized that GDC-0980 would potentiate an anti-tumor effect when combined with the PARP inhibitor, ABT888 and carboplatin.

Methods: Athymic mice bearing TNBC xenograft tumors were treated with GDC-0980 alone or in combination with ABT888 and carboplatin. Mechanism-based in vitro studies using a panel of 5-7 BRCA-wt/mutants TNBC cell lines (HCC1937, MDA-MB231, MDA-MB468, BT20, SUM149) were performed.

Results: GDC-0980 in combination with ABT888 plus carboplatin blocked the growth of established xenograft tumors by 80-90% with a concomitant increase in cl-caspse3, and a decrease in tumor Ki67, pVEGFR, CD31, p4EBP1, and pS6RP IHC-levels. Mechanistically, GDC-0980 treatment increased pgH2AX (WB, IF), caused gain in PAR and a subsequent sensitization of TNBC cells to ABT888 plus carboplatin in a time-dependent manner. The treatment (1) decreased proliferation signals (pAKT, pP70S6K, p4EBP1, pS6RP), PAR/PARP, PAR/pgH2AX, live/dead cell ratios, cell cycle progression and clonogenic 3D growth, and (2) increased apoptosis markers (cl-caspase3, 9, BIM, cl-PARP, and annexinV positivity). Three-dimensional projection movies showed that (1) GDC-0980 alone attenuated nuclear pgH2AXS139 foci in MDA-MB468 cells at 24 hours and (2) cytoplasmic cl-caspase3 increased and nuclear Ki67 decreased following GDC-0980+ABT888+carboplatin in MDA-MB468 cells at 72 hours.

Conclusion: Our data revealed that PI3K-mTOR pathway inhibition enhances the antitumor efficacy of PARP inhibitor in the presence of carboplatin by inhibiting the DDR system in conjunction with the inhibition of pro-proliferative and anti-apoptotic signals.

Citation Format: Nandini Dey, Jennifer H. Carlson, Yuliang Sun, Lori S. Friedman, Pradip De, Brian Leyland-Jones. DDR-mediated antitumor actions of PARP inhibitor: Can PI3K-mTOR pathway inhibitor be combined with PARP inhibitor in TNBT? [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A16.
Abstract A31: Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation
Authors: Shah Supriya , Lee Joyce V. , Carrer Alessandro , Snyder Nathaniel W. , Wellen Kathryn E.
Published: October 2015

Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl-CoA availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA: coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase (ACLY), and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.

Citation Format: Supriya Shah, Joyce V. Lee, Alessandro Carrer, Nathaniel W. Snyder, Kathryn E. Wellen. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A31.
Abstract A36: Combined inhibition of PI3K isoforms and mTOR kinase is critical for cancer stem cell inhibition by VS-5584
Authors: Kolev Vihren N. , Wright Quentin G. , Weaver David T. , Padval Mahesh V. , Pachter Jonathan A. , Xu Qunli
Published: October 2015

Cancer stem cells (CSCs) have been implicated in resistance to anticancer therapies, disease recurrence, and metastasis, which represent major challenges in the clinical management of cancer. Therapeutic targeting of CSCs thus holds promise in addressing these challenges. VS-5584 is a selective dual PI3K/mTOR kinase inhibitor that potently inhibits mTORC1, mTORC2 and all four Class I PI3K isoforms. We report here that VS-5584 is up to 30-fold more potent at inhibiting the proliferation and survival of CSCs than non-CSCs in breast cancer cell lines using multiple orthogonal CSC assays. Moreover, VS-5584 preferentially induced apoptosis in Aldefluor-positive CSCs relative to Aldefluor-negative non-CSCs as measured by Annexin V and Caspase 3/7 assays. In contrast, paclitaxel induced more apoptosis in non-CSCs than CSCs cells. VS-5584 also preferentially diminished CSCs in human breast and small cell lung cancer xenograft models in vivo, as evidenced by marked reduction of tumor-initiating capacity in an in vivo limiting dilution re-implantation assay. Likewise, ex vivo VS-5584 treatment of surgically removed breast and ovarian patient tumors preferentially reduced CSC populations. In contrast, cytotoxic chemotherapeutic agents such as paclitaxel and cisplatin preferentially eliminate non-CSCs and thus enrich the CSC population. Interestingly, preferential targeting of CSCs requires inhibition of multiple components of the PI3K/mTOR pathway; simultaneous knockdown of PI3Kα, PI3Kβ, and mTOR by siRNA phenocopied the effect of VS-5584 and exhibited the strongest preferential targeting of CSCs, while knocking down of individual PI3K isoform or mTOR failed to do so. Consistent with its strong suppression of CSCs, VS-5584 effectively delayed tumor regrowth following chemotherapy in small cell lung cancer xenograft models including a patient-derived primary tumor model. The preferential targeting of CSCs thus prompts a new paradigm for testing VS-5584 in the clinic: clinical trials designed with CSC-directed endpoints may facilitate demonstration of the therapeutic benefit of VS-5584 at well-tolerated doses and thus enable an optimal therapeutic window. Furthermore, suppression of CSCs by VS-5584 in combination with other agents that target the bulk tumor may represent an appealing strategy to achieve more durable responses for cancer patients.

Citation Format: Vihren N. Kolev, Quentin G. Wright, David T. Weaver, Mahesh V. Padval, Jonathan A. Pachter, Qunli Xu. Combined inhibition of PI3K isoforms and mTOR kinase is critical for cancer stem cell inhibition by VS-5584. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A36.
Abstract A43: Basal expression of insulin-like growth factor 1 receptor determines intrinsic resistance of cancer cells to a PI3K inhibitor ZSTK474
Authors: Isoyama Sho , Kajiwara Gensei , Tamaki Naomi , Mutsumi Okamura , Yoshimi Hisashi , Nakamura Naoki , Nishimura Yumiko , Yamori Takao , Dan Shingo
Published: October 2015

Drug resistance often critically limits the efficacy of molecular targeted drugs. Although pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) is an attractive therapeutic strategy for cancer therapy, molecular determinants for efficacy of PI3K inhibitors remain unclear. We previously identified that overexpression of insulin-like growth factor 1 receptor (IGF1R) contributed to the development of drug resistance after long-term exposure to PI3K inhibitors. In this study, we examined the involvement of basal IGF1R expression in intrinsic resistance of drug-naïve cancer cells to PI3K inhibitors and whether inhibition of IGF1R overcomes the resistance. We found that cancer cells highly expressing IGF1R exhibited resistance to dephosphorylation of Akt and subsequent antitumor effect by ZSTK474 treatment. Knockdown of IGF1R by siRNAs facilitated the dephosphorylation and enhanced the drug efficacy. These cells expressed tyrosine-phosphorylated IRS-1 in high levels, which was dependent on basal IGF1R expression. In these cells, combination with the IGF1R-TKI, OSI-906, improved the efficacy of ZSTK474 in vitro and in vivo. Finally, we found a significant correlation between the basal expression level of IGF1R and the inefficacy of ZSTK474 in in vivo human cancer panel, as well as in vitro. These results suggest that basal IGF1R expression affects intrinsic resistance of cancer cells to ZSTK474, and IGF1R is a promising target to improve the therapeutic efficacy. The current results provide evidence of combination therapy of PI3K inhibitors with IGF1R inhibitors for treating IGF1R-positive human cancers.

Citation Format: Sho Isoyama, Gensei Kajiwara, Naomi Tamaki, Okamura Mutsumi, Hisashi Yoshimi, Naoki Nakamura, Yumiko Nishimura, Takao Yamori, Shingo Dan. Basal expression of insulin-like growth factor 1 receptor determines intrinsic resistance of cancer cells to a PI3K inhibitor ZSTK474. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A43.
Abstract A47: DNA-PKcs is amplified in high-grade serous ovarian cancer (HGSC), correlates with poor outcome and drives resistance to platinum therapy via the AKT signaling pathway
Authors: Curry Edward , Cheraghchi-Bashi-Astaneh Azadeh , Chen Michelle , Cunnea Paula , Camila De Sousa , Maginn Elaina , Dai Yan , Liu Edison , Wasan Harpreet , Mills Gordon B. , Bowtell David , Gabra Hani , Stronach Euan A.
Published: October 2015

High grade serous ovarian cancer is typified by p53 mutation, high degrees of genomic instability and the development of chemo-resistance. Genomic translocations result from incorrectly repaired DNA double strand breaks (DSBs). DNA-PKcs is a central catalytic component of the error prone non-homologous end joining (NHEJ) DSB repair mechanism. We report here that DNA-PKcs is frequently amplified in copy number in HGSC and that amplification correlates with higher DNA-PKcs gene expression and poorer patient outcome using both in-house and publicly available datasets. Targeting DNA-PKcs, pharmacologically or by RNAi, enhances apoptosis in response to platinum treatment in platinum resistant cell lines and primary models and inhibition of DNA-PK restores response to cisplatin in chemoresistant ovarian cancer cells in vivo. SKOV-3 tumor xenografts were implanted subcutaneously into Balb/c Nu/Nu mice and treated with DNA-PKcs inhibitor NU7441 for 2 weeks alone or in combination with cisplatin. DNA-PK inhibition or cisplatin treatment alone were ineffective however in combination they decreased tumor growth at 14 days by 90%, relative to platinum only treatment. On investigating the mechanism of DNA-PKcs mediated chemoresistance we revealed that, in response to DNA damage, DNA-PKcs phosphorylates AKT on serine residue 473 in platinum resistant ovarian tumor cells, but not sensitive cells from the same patient. Phosphorylation at AKT threonine 308 is unaffected and DNA-PK inhibition does not interfere with insulin-mediated phosphorylation of AKT S473. DNA-PK mediated AKT activation in chemoresistant cells results in inhibitory phosphorylation of the pro-apoptotic protein BAD and stabilization of the anti-apoptotic Bcl-2 protein resulting in the observed attenuation of apoptotic response to platinum treatment. DNA-PK inhibition is an attractive therapeutic strategy for resensitizing resistant tumors to platinum based therapy, directly linking the DNA damage caused by platinum to pro-survival AKT pathway signaling.

Citation Format: Edward Curry, Azadeh Cheraghchi-Bashi-Astaneh, Michelle Chen, Paula Cunnea, De Sousa Camila, Elaina Maginn, Yan Dai, Edison Liu, Harpreet Wasan, Gordon B. Mills, David Bowtell, Hani Gabra, Euan A. Stronach. DNA-PKcs is amplified in high-grade serous ovarian cancer (HGSC), correlates with poor outcome and drives resistance to platinum therapy via the AKT signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A47.
Abstract B06: The roles of FoxO transcription factors in mediating AKT activation and renal tumor growth in response to pharmacological inhibition of the PI3K-AKT pathway
Authors: Gan Boyi
Published: October 2015

The PI3K-AKT pathway is hyperactivated in many human cancers, and several drugs to inhibit this pathway are currently being tested in various pre-clinical and clinical trials. It has been shown that pharmacological inhibition of the PI3K-AKT pathway results in feedback activation of other oncogenic signaling pathways, which likely will limit the clinical utilization of these inhibitors in cancer treatment. However, the underlying mechanisms of such feedback regulation remain incompletely understood.

The PI3K-AKT pathway is a validated therapeutic target in renal cell carcinoma (RCC). Here we show that FoxO transcription factors serve to promote AKT phosphorylation at Ser473 in response to the treatment of NVP-BEZ235, a PI3K/mTOR dual inhibitor, in renal cancer cells. Inactivation of FoxO attenuated NVP-BEZ235-induced AKT Ser473 phosphorylation, and rendered renal cancer cells more susceptible to NVP-BEZ235-mediated cell growth suppression in vitro and tumor shrinkage in vivo. Mechanistically, we showed that FoxOs upregulated the expression of Rictor, an essential component of mammalian target of rapamycin complex 2 (mTORC2), in response to NVP-BEZ235 treatment, and revealed that Rictor is a key downstream target of FoxOs in NVP-BEZ235-mediated feedback regulation. We also show that FoxOs similarly modulate the feedback response on AKT Ser473 phosphorylation and renal tumor growth by the treatment of other PI3K or AKT inhibitors, such as MK-2206. Together, our study reveals a novel mechanism of PI3K-AKT inhibition-mediated feedback regulation.

Importantly, a recent RCC clinical trial with MK-2206 revealed a dichotomous response in renal cancer patients: a subset of patients had dramatic tumor reduction, while another subset of RCC patients showed no decrease in tumor growth rate, and had a very short progression free survival. We will discuss our work to determine the expression/activation status of the FoxO-Rictor-AKT signaling axis in renal cancer patients receiving AKT inhibitor treatment, which may identify FoxO as a novel biomarker to stratify RCC patients for PI3K or AKT inhibitor treatment.

Citation Format: Boyi Gan. The roles of FoxO transcription factors in mediating AKT activation and renal tumor growth in response to pharmacological inhibition of the PI3K-AKT pathway. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B06.
Abstract B07: Estrogen-related receptor alpha regulates S6K1 expression and tamoxifen sensitivity in breast cancer
Authors: Manna Subrata , Bostner Josefine , Alayev Anya , Stal Olle , Holz Marina K.
Published: October 2015

Estrogen related receptor alpha (ERRα) is an orphan nuclear receptor that plays important role in the metabolic activities and proliferation of cancer cells. We investigated the role of ERRα in regulating the expression of S6K1 in breast cancer cells. First, using RT-qPCR and immunoblotting we found that ERRα overexpression in estrogen receptor (ER) positive MCF7 cells results in decreased S6K1 expression and activity. Conversely, downregulation of ERRα expression resulted in increased S6K1 expression and activity in ER-negative MDA-MB-231 cells. Second, overexpression of ERRα in MCF7 cells also resulted in decreased transcriptional activity of the RPS6KB1 gene promoter as revealed by luciferase reporter assay. On the other hand, ERRα knockdown in MDA-MB-231 cells resulted in increased promoter activity. Third, because the proximal 1 kilobase (Kb) promoter region of S6K1 contains several putative estrogen receptor DNA binding elements (EREs), we investigated whether ERRα modulates S6K1 expression by direct promoter binding using chromatin immunoprecipitation (ChIP) technique. We detected two binding peaks approximately 300 and 600 kb away from the transcription start site (TSS). In addition, we showed that downregulation of ERRα caused increased cell proliferation and sensitivity to the mTOR inhibitor rapamycin. Suprisingly, tamoxifen treatment increased the proliferative capacity of these cells. Interestingly, cytoplasmic and nuclear staining of ERRα in tumor specimens derived from patients in the Stockholm breast cancer trial of adjuvant tamoxifen revealed that (1) in triple-negative tumors, the low-expressing cytoplasmic ERRα group had a worse prognosis, whereas a clear improvement in recurrence-free survival was found in the group with high ERRα-expressing tumors; and (2) in the ERα-negative subgroup, high ERRα rendered a clear tamoxifen benefit, which is very interesting, as this group is not receiving tamoxifen today and may constitute a subgroup which could gain from tamoxifen. Overall, our data indicate that ERRα regulates S6K1 expression and affects the sensitivity to rapamycin tamoxifen. Our long-term goal is to establish ERRα as a marker for endocrine and rapamycin therapy response, as well as a novel target in combination therapy approaches.

Citation Format: Subrata Manna, Josefine Bostner, Anya Alayev, Olle Stal, Marina K. Holz. Estrogen-related receptor alpha regulates S6K1 expression and tamoxifen sensitivity in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B07.
Abstract B15: Mapping topology of PI3K/AKT/mTOR signaling in glioblastoma molecular subgroups
Authors: Joy Anna , Ramesh Archana , Smirnov Ivan , Reiser Mark , Mills Gorden , Kim Seungchan , Feuerstein Burt
Published: October 2015

Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features and mapped their PI3K/AKT pathway topology. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Evidence indicates one subtype is very sensitive to BCNU or CCNU. A key question is whether oncogene drivers differ in subgroups. We developed a new method to map topology of oncogene signaling in vivo using TCGA reverse phase protein array data. Our evidence indicates topology of PI3K/AKT/mTOR signaling varies between subgroups suggesting sensitivity to pathway inhibitors will differ. AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subgroups will help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.

Note: This abstract was not presented at the conference.

Citation Format: Anna Joy, Archana Ramesh, Ivan Smirnov, Mark Reiser, Gorden Mills, Seungchan Kim, Burt Feuerstein. Mapping topology of PI3K/AKT/mTOR signaling in glioblastoma molecular subgroups. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B15.
Abstract B55: mTOR signaling is critical to the development and expansion of preneoplastic foci in a rodent model of progenitor-marker positive hepatocellular carcinoma
Authors: Francois-Vaughan Heather , Brilliant Kate , Adebayo Adeola O. , Parry Nicola M.A. , Gruppuso Philip A. , Sanders Jennifer A.
Published: October 2015

Hepatocellular carcinoma is a heterogeneous disease with distinct tumor sub-types based on expression of markers for hepatocytes and adult liver progenitor cells, also known as oval cells. HCCs expressing progenitor cell markers have a poor prognosis. Relatively little is known about the signaling pathways underlying the molecular pathogenesis of these tumors. We have previously identified the mTOR pathway as playing a critical role in the proliferation of oval cells in rodents. In this study, we investigated the temporal activation of mTOR in a rodent animal model of progenitor marker-positive HCC. Rats were placed on the Solt-Farber protocol to induce hepatic carcinogenesis and mTOR activity assessed in preneoplastic and persistent focal lesions. Robust mTORC1 activity was found in early preneoplastic focal lesions with persistent focal lesions displaying minimal mTOR activity. Continuous administration of rapamycin resulted in a significant decrease in focal lesion burden, but led to an increase in PI3K signaling. Administration of rapamycin during the window of maximal mTOR activation significantly reduced focal lesion burden that was indistinguishable from that seen with continuous rapamycin administration. However, unlike continuous administration, short-term rapamycin administration did not result in compensatory activation of either PI3K or Erk1/2 signaling. We have also characterized the effect of short-term mTOR inhibition on the gene expression signature of the persistent preneoplastic foci. We conclude that mTOR activation is critical to the expansion and promotion of preneoplastic focal lesions in a rodent model of progenitor marker-positive HCC. These results raise the possibility that inhibition of mTOR early in the process of progenitor-derived hepatic carcinogenesis might serve as an effective preventative strategy for HCC.

Citation Format: Heather Francois-Vaughan, Kate Brilliant, Adeola O. Adebayo, Nicola M.A. Parry, Philip A. Gruppuso, Jennifer A. Sanders. mTOR signaling is critical to the development and expansion of preneoplastic foci in a rodent model of progenitor-marker positive hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B55.
Abstract IA01: Targeting phosphoinositide 3-kinase for cancer therapy
Authors: Cantley Lewis C.
Published: October 2015

Phosphoinositide 3-kinase (PI3K) is a central enzyme in a signaling pathway that mediates cellular responses to insulin and other growth factors. The signaling pathway involving insulin, PI3K and the downstream components of AKT and mTOR is highly conserved from worms and flies to humans and genetic analysis of the pathway has revealed a conserved role in regulating glucose metabolism and cell growth. Germline mutational events that lead to hyperactivation of the PI3K pathway result in hamartoma syndromes and cancers. Sporadic activating mutations in PIK3CA, encoding the p110alpha catalytic subunit of PI3K or inactivating mutations in PTEN, a phosphoinositide 3-phosphatases that reverses the effects of PI3K, are among the most common events in solid tumors. More than thirty drugs that target PI3K and other components of this pathway are in clinical trials for a variety of cancers. It is likely that PI3K pathway inhibitors will need to be combined with other drugs to be broadly effective. We have employed genetically engineered mouse models that develop cancers due to mutations in genes in the PI3K pathway and are using these models to explore the efficacy of PI3K pathway inhibitors as single agents or in combination with other drugs. The role of PI3K inhibitors for treating cancers in these mouse models and in human trials will be discussed.

Citation Format: Lewis C. Cantley. Targeting phosphoinositide 3-kinase for cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA01.
Abstract IA12: New roles for PI3K isoforms in cancer
Authors: Vanhaesebroeck Bart
Published: October 2015

The PI3K pathway has been implicated in a variety of physiological responses, and is a therapeutic target in cancer and inflammation. Mammals have 8 distinct isoforms of PI3K. In order to gain insight into the physiological roles of PI3K isoforms, we have created ‘kinase knockin’ mice with germline inactivating or activating mutations in PI3K isoforms. This strategy more faithfully mimics pharmacological inhibitors or oncogenic activation than the classical KO/transgenic approaches, and has allowed us to uncover isoform-selective roles of class I isoforms of PI3K. An update on these efforts will be provided, uncovering new potential roles for PI3K isoforms in cancer therapy.

Citation Format: Bart Vanhaesebroeck. New roles for PI3K isoforms in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA12.
Abstract IA13: Targeting PI3K isoforms in cancer: From mouse genetics to human therapy
Authors: Zhao Jean J.
Published: October 2015

The signaling axis of the class-I phosphatidylinositol 3-kinase (PI3K) is perhaps most commonly activated in cancer; activation of this pathway occurs via distinct mechanisms that include somatic activating mutations in PIK3CA (the gene encoding the p110α isoform of PI3K), genetic or epigenetic loss of the PTEN tumor suppressor and mutation/overexpression of RTKs. Thus PI3K represents an attractive target for cancer therapy and tremendous efforts are being devoted to developing effective PI3K inhibitors for cancer treatment. There are several PI3K isoforms in mammals, only the p110α and p110β isoforms are ubiquitously expressed. While the majority of the signal downstream of nearly all the RTKs and oncogenes so far tested is carried through p110α, p110β appears to play a prominent role in G protein mediated signaling in cells and for RTK signaling in certain circumstances. Surprisingly, we found that p110β is also the major player in a number of tumors driven by PTEN loss. In the mouse, each enzyme has been found to be necessary for certain processes and dispensable for others. Taking both genetic and pharmacological approaches, we have found that the two isoforms can actually play opposing roles in the normal development and pathology of mammary tissue. More recently, we found that p110α and p110β isoforms play spatially distinct roles in the epidermal skin that are required for the development and maintenance of PTEN hamartoma tumor syndrome. In this talk, I will discuss our most recent results on our studies of the distinct roles of the two isoforms in cancer.

Citation Format: Jean J. Zhao. Targeting PI3K isoforms in cancer: From mouse genetics to human therapy. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA13.
Abstract IA16: Mechanisms of resistance to mTOR inhibitors in leukemia and lymphoma
Authors: Vo Thanh-Trang , Lee Jong-Hoon Scott , So Lomon , Beagle Brandon , Janes Matthew R. , Fruman David A.
Published: October 2015

Targeting mTOR signaling is a promising approach for treating blood cancers. We reported that mTOR kinase inhibitors, including PP242 and MLN0128, synergize with ABL tyrosine kinase inhibitors (TKIs) to cause cell cycle arrest and death in acute leukemia cells driven by BCR-ABL. mTOR kinase inhibitors are more effective than rapamycin in these models and have minimal effects on normal hematopoietic cells and immune responses at anti-leukemic doses. Ongoing studies indicate that mTOR kinase inhibitors are immunosuppressive at slightly higher concentrations. Moreover, the compounds are generally not cytotoxic as single agents in leukemia or lymphoma models. These findings emphasize the need for rational combinations to unleash the therapeutic potential of mTOR kinase inhibitors. To this end, we have tested various classes of anti-cancer agents guided by gene expression and proteomic data. Our data reveal synergies between mTOR kinase inhibitors with histone deacetylase inhibitors in B-ALL, and with BCL2 antagonists in DLBCL. Unexpectedly, mTOR kinase inhibitors protect B-ALL cells from methotrexate and 6-mercaptopurine, chemotherapeutic agents used in the treatment of B-ALL patients. ABL TKIs can also protect B-ALL cells from methotrexate by inhibiting downstream mTOR signaling. Together these studies identify potential applications and limitations of mTOR-targeted therapy in blood cancers.

Citation Format: Thanh-Trang Vo, Jong-Hoon Scott Lee, Lomon So, Brandon Beagle, Matthew R. Janes, David A. Fruman. Mechanisms of resistance to mTOR inhibitors in leukemia and lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA16.
Abstract IA19: Targeting PI3K-δ and PI3K-γ in hematological malignancies with duvelisib (IPI-145)
Authors: Adams Julian
Published: October 2015

PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes where they have distinct and mostly non-overlapping roles in immune cell function and important roles in the biology of B-cell neoplasms. Duvelisib (IPI-145), a potent, orally available, small molecule inhibitor of PI3K-δ and PI3K-γ, was designed to investigate the hypothesis that simultaneous inhibition of these two specific isoforms would demonstrate broad adaptive and innate immune cell inhibitory activity and enhanced efficacy in hematologic malignancies as well as inflammatory and autoimmune diseases. Biochemical, target occupancy, cellular, and whole blood assays indicate that the inhibition of both the PI3K-δ and PI3K-γ isoforms with duvelisib can be accomplished effectively at clinically relevant concentrations. Duvelisib displays single-agent activity across a spectrum of hematologic neoplasm cell lines and potently inhibits the in vitro proliferation of primary human CLL cells. In certain tumor cell lines, the combination of isoform selective PI3K-δ and PI3K-γ inhibitors demonstrated synergy, suggesting that combined inhibition of both PI3K-δ and PI3K-γ results in greater growth suppression than the inhibition of either isoform alone. In addition, a high throughput combination screen demonstrates synergy between duvelisib in combination with multiple classes of approved and investigational compounds in hematologic malignancies represented by a broad panel of tumor cell lines. Duvelisib is currently in late-stage development for the treatment of hematologic malignancies including iNHL and CLL. Inhibition of both the PI3K-δ and PI3K-γ isoforms targets the malignant cells as well as their microenvironment, suggesting a rationale for the favorable response rates reported in iNHL and CLL patients administered duvelisib.

Citation Format: Julian Adams. Targeting PI3K-δ and PI3K-γ in hematological malignancies with duvelisib (IPI-145). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA19.
Abstract PR02: Targeting PI3K: The PIP2 binding site
Authors: Miller Michelle , Schmidt-Kittler Oleg , Bolduc David M. , Brower Evan T. , Chaves-Moreira Daniele , Allaire Marc , Kinzler Kenneth W. , Jennings Ian G. , Thompson Philip E. , Cole Philip A. , Amzel L. Mario , Vogelstein Bert , Gabelli Sandra B.
Published: October 2015

Structural biology has yielded many significant insights into inhibitor binding and isoform selectivity, directing the design of many important clinical candidates. To date, structural studies have focused on the ATP-binding site and ATP-competitive inhibitors. We have recently determined the structure of PI3Kα; in complex with the soluble lipid substrate mimetic, diC4-PIP2. The substrate binds in a positively charged pocket, defined by the activation and P-loops of the kinase domain, and the iSH2 domain of p85. The positively charged residues responsible for binding PIP2 that are present on the activation loop of Class I PI3K are missing in Class II and III PI3K. This explains why these two classes have lower affinity for PIP2. The complex structure provides insights into the catalysis and regulation of PI3K. Key interactions between the activation loop and nSH2 domain may modulate active and inactive conformations of the enzyme upon the binding of phosphorylated receptor tyrosine kinases. In addition, a second lipid substrate was identified in the structure. It binds in a hydrophobic pocket between the Adaptor Binding Domain (ABD), kinase domain and iSH2 domain of p85. Fluorescence quenching studies confirm the ability of PI3K to bind an additional PIP2 molecule.

This abstract is also being presented as Poster B17.

Citation Format: Michelle Miller, Oleg Schmidt-Kittler, David M. Bolduc, Evan T. Brower, Daniele Chaves-Moreira, Marc Allaire, Kenneth W. Kinzler, Ian G. Jennings, Philip E. Thompson, Philip A. Cole, L. Mario Amzel, Bert Vogelstein, Sandra B. Gabelli. Targeting PI3K: The PIP2 binding site. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr PR02.