bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
Abstract A04: Menopausal vasomotor symptoms and incident breast cancer risk in the Study of Women's Health Across the Nation
Authors: Hart Vicki , Sturgeon Susan , Reich Nicholas , Sievert Lynnette Leidy , Crawford Sybil , Gold Ellen , Avis Nancy , Reeves Katherine W. 
Published: October 2015

Abstract
Two previous retrospective studies reported a significantly decreased breast cancer risk among women who experienced menopausal vasomotor symptoms (VMS). It is possible that VMS are a marker of declining sex hormone levels during menopause. Elevated sex hormone levels have been associated with increased breast cancer risk, suggesting that VMS may be indicative of lower susceptibility to breast cancer. We evaluated this relationship in the prospective Study of Women's Health Across the Nation (SWAN), which includes annual data on VMS and endogenous hormone levels for 3,098 women who were pre- or early peri-menopausal at enrollment. We evaluated the effect of VMS on breast cancer risk using discrete survival analysis. Over an average 11.4 years of follow-up, 129 breast cancer cases were self-reported and approximately 50% of participants reported some VMS. Women reporting VMS at any current or previous visit had a reduced risk of breast cancer compared to those never experiencing VMS (OR 0.63, 95% CI 0.39, 1.02). Results were strengthened in the subgroup of women who fully transitioned to postmenopausal during follow-up (N=80 cases, OR 0.45, 95% CI 0.26, 0.77). Associations were unchanged upon adjustment for endogenous hormone levels. VMS appear to be a marker of reduced breast cancer risk. Future research is needed to fully understand this relationship, which does not appear to be mediated by endogenous hormone levels.
Citation Format: Vicki Hart, Susan Sturgeon, Nicholas Reich, Lynnette Leidy Sievert, Sybil Crawford, Ellen Gold, Nancy Avis, Katherine W. Reeves. Menopausal vasomotor symptoms and incident breast cancer risk in the Study of Women's Health Across the Nation. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A04.