bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B31: Targeting PI3K and RAS pathways in a novel preclinical model of prostate cancer
Authors: Pearson Helen B. , Humbert Patrick O. , Phillips Wayne A. 
Published: October 2015

Abstract
Oncogenic activation of the PI3K cascade increases cell proliferation, survival, and migration to facilitate tumor growth in many human cancers, including prostate cancer. Prostate cancer is the second major cause of cancer-related deaths in men globally, reflecting resistance to standard clinical regimens (i.e. androgen ablation, radiation, and chemotherapy). To better understand the role of the PI3K pathway in the initiation, progression and treatment of prostate cancer we have developed a novel mouse model of prostate cancer by expressing a single activating mutation in Pik3ca, the gene coding for the p110α catalytic subunit of PI3K, in the prostate.
To generate the model we have used a mouse with a conditional (Cre recombinase-inducible) knock-in of the common activating mutation, Pik3caH1047R, expressed from the endogenous locus and targeted the mutation to the prostate gland by crossing this mouse to mice expressing Cre under the control of prostate-specific promoter PB. Histological analysis of mice expressing Pik3caH1047R in their prostate revealed flat and cribriform hyperplastic lesions at 200 d, which progressed to locally invasive carcinoma at 400 d. This data demonstrates that a heterozygous activating mutation in Pik3ca is sufficient to cause invasive prostate cancer. Furthermore, we show that mice co-expressing heterozygous Pik3ca and KRas oncogenic mutations in the prostate display accelerated progression to invasive prostate carcinoma (100% incidence) compared to single mutants, demonstrating a synergistic relationship between these two oncogenic events.
We then used this model to perform a preclinical trial to assess the therapeutic efficacy of TORC1, panPI3K/mTORC1 and MEK inhibitors, either alone or in combination, in prostate cancer. Our results show that the combination of MEK and PI3K/mTOR inhibitors has superior efficacy compared to all other combinations or single agents assessed and with no sign of toxicity.
Our data provide strong evidence that simultaneously targeting both the PI3K and RAS pathways in advanced prostate cancer patients may prove to hold enhanced therapeutic outcome.
Citation Format: Helen B. Pearson, Patrick O. Humbert, Wayne A. Phillips. Targeting PI3K and RAS pathways in a novel preclinical model of prostate 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 B31.
Abstract B38: p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer
Authors: Eichhorn Pieter J.A. , Serra Violeta , Garcia-Garcia Celina , Ibrahim Yasir H. , Prudkin Lumilla , Parra Josep-Lluis , Prat Aleix , Hahn William C. , Kim So Young , Baselga Jose 
Published: October 2015

Abstract
The PI3K signaling pathway regulates diverse cellular processes including proliferation, survival and metabolism and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncover potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mTOR blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.
Citation Format: Pieter J.A. Eichhorn, Violeta Serra, Celina Garcia-Garcia, Yasir H. Ibrahim, Lumilla Prudkin, Josep-Lluis Parra, Aleix Prat, William C. Hahn, So Young Kim, Jose Baselga. p90RSK mediates resistance to PI3K-pathway inhibitors 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 B38.
Abstract IA02: G-proteins regulating PI3Ks and PI4KIIIβ regulating a G-protein
Authors: Burke John E. , Inglis Alison J. , Vadas Oscar , Perisic Olga , Masson Glenn R. , McLaughlin Stephen H. , Williams Roger L. 
Published: October 2015

Abstract
Dysregulation of phosphoinositide levels is associated with many cancer phenotypes. A variety of mechanisms activate phosphoinositide 3-kinases (PI3Ks), including association with G-proteins. Increased activity of PI 4-kinases (PI4Ks) also has been associated with cancer phenotypes. Although PI4Ks associate with G proteins, the relationship with enzyme activity is more complex. To understand regulation of these enzymes, we have used hydrogen/deuterium exchange mass spectrometry (HDX-MS) in conjunction with X-ray crystallography. The method enables us to explore not only three-dimensional structures but also the dynamics of the activation process and to map key regulatory interactions with G-proteins.
PI3Ks and PI4Ks, along with PI3K-related protein kinases such as TOR are members of a closely related family that all have a common core structure, consisting of a helical domain closely associated with a kinase domain. The helical domains have important roles both in stabilizing the structures and forming regulatory interactions. For example, PI3Kγ is activated by associating with Gβγ heterodimers released upon activation of GPCRs, and HDX-MS shows how the helical domain of the enzyme interacts with the p101 regulatory subunit and with Gβγ heterodimers. When the p110γ/p101 complex interacts with lipid membranes a conformational change takes place that prepares the helical domain for association with prenylated Gβγ heterodimers on membranes.
Type IIIβ PI4K (PI4KB) synthesizes PI4P on Golgi membranes. The enzyme is important for processes that require rapid expansion and remodeling of PI4P-containing membranes, including replication of a range of viruses. Its activity has also been associated with decreased cell-cell adhesion in invasive cancer cell lines. Using both HDX-MS and X-ray crystallography we have shown how the helical domain of PI4KB interacts with the Ras superfamily G protein Rab11. In this unique interaction, PI4KB grasps the Rab11 but leaves the switch regions of the G protein unencumbered and free to interact with Rab11 effectors. Consistent with this type of interaction, PI4K can interact with complexes of Rab11 bound to both GDP and GTP. Furthermore, the structure of the complex of the Rab11 effector FIP3 bound to the Rab11-PI4KB complex shows that PI4KB does not perturb Rab11 effector binding and suggests that PI4KB may be able to recruit both Rab11 and its downstream effectors to Golgi membranes.
Citation Format: John E. Burke, Alison J. Inglis, Oscar Vadas, Olga Perisic, Glenn R. Masson, Stephen H. McLaughlin, Roger L. Williams. G-proteins regulating PI3Ks and PI4KIIIβ regulating a G-protein. [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 IA02.
Abstract IA10: Nuclear PTEN in regulation of genome integrity
Authors: Stambolic Vuk 
Published: October 2015

Abstract
Loss of PTEN function has been implicated in the etiology of numerous human malignancies, including sporadic brain, prostate, thyroid, breast, uterine and kidney tumors. PTEN germline have also been found in patients with PHTS, an autosomal-dominant cancer predisposition syndrome. Despite a thorough understanding of the inhibitory role for PTEN in the PI3K pathway, acting as a 3′PI phosphatase and directly antagonizing PI3'K, relatively little is known about PTEN's functions in the nucleus, a cellular compartment where it also resides. Our recent work has uncovered a nuclear function of PTEN in tumor suppression, which is independent from its 3′PI-phosphatase activity, but relies on PTEN protein phosphatase activity. Nuclear PTEN, which is SUMOylated, plays a prominent role in homologous recombination-based DNA repair, acting downstream of the protein kinase ATM. PTEN-deficient cells and tumors are impaired in their response to DNA damage and display heightened sensitivity to genotoxic agents, which may have significant implications for the treatment of PTEN-deficient cancers.
Citation Format: Vuk Stambolic. Nuclear PTEN in regulation of genome integrity. [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 IA10.
Abstract IA11: Targeting PI3K-mTOR signaling in glioblastoma: A central role for mTORC2 in drug resistance and metabolic reprogramming
Authors: Mischel Paul 
Published: October 2015

Abstract
Metabolic reprogramming is a central hallmark of cancer, enabling tumor cells to obtain the macromolecular precursors and energy needed for rapid tumor growth. mTOR plays a central role in this process. Understanding how mTOR coordinates metabolic reprogramming may yield new insights into tumor pathogenesis, and provide a landscape of promising drug targets, while yielding important clues into mechanisms of resistance to the signal transduction inhibitors currently in use. This talk will focus on the emerging central regulatory role for mTOR complex 2 (mTORC2) in cancer metabolic reprogramming and targeted therapy resistance highlighting a recently identified, novel, Akt-independent, c-Myc-dependent pathway.
Citation Format: Paul Mischel. Targeting PI3K-mTOR signaling in glioblastoma: A central role for mTORC2 in drug resistance and metabolic reprogramming. [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 IA11.
Abstract IA17: The therapeutic potential of PI(3) inhibition in lymphoma
Authors: Staudt Louis M. 
Published: October 2015

Abstract
The PI(3) kinase is engaged by multiple genetic, epigenetic and signaling abnormalities that are unique to particular molecular subtypes of lymphoma. Central to our understanding of lymphomas is signaling from the B cell receptor (BCR), which can occur by different mechanisms in each lymphoma subtype. A natural consequence of BCR signaling is engagement, which activates the SYK tyrosine kinase and consequently PI(3) kinase. The ABC subtype of diffuse large B cell lymphoma has chronic active BCR signaling in which PI(3) kinase is engaged along with NF-κB, both of which promote the survival of the malignant cells. In Burkitt lymphoma, a different mode of BCR signaling, known as tonic signaling, is responsible for cell survival and this is entirely mediated by the PI(3) kinase, with little or no involvement of NF-κB. A small subset of lymphomas belonging to the GCB subtype of DLBCL also appears to utilize tonic BCR signaling for survival. However, over half of GCB DLBCL tumors activate PI(3) kinase signaling due to genetic and epigenetic mechanisms, including PTEN inactivation and amplification of the mIR-17-92 cluster of microRNAs, which negatively regulate PTEN. Normal and malignant B cells express the PI(3) kinase delta catalytic subunit, which is not expressed highly outside of the lymphoid lineage. Selective PI(3) kinase delta inhibition with idelalisib has produced objective responses in several lymphoma malignancies. An open question, however, is whether other PI(3) kinase isoforms also contribute to signaling in lymphoma. Successful treatment of lymphomas with PI(3) kinase inhibitors will require drug combinations that inactivate parallel survival mechanisms. For example, in ABC DLBCL, PI(3) kinase inhibition synergizes strongly with inhibition of NF-κB using the BTK inhibitor ibrutinib.
Citation Format: Louis M. Staudt. The therapeutic potential of PI(3) inhibition in 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 IA17.
Abstract IA22: Targeting mTOR for breast cancer therapy
Authors: Meric-Bernstam Funda 
Published: October 2015

Abstract
The Phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway plays a central role in cell metabolism, growth, proliferation, and survival. Activation of PI3K/Akt/mTOR signaling contributes to the oncogenesis of many tumor types, and thus the pathway is being actively pursued as a promising therapeutic target. mTOR, an important component of this pathway, exists in two multiprotein complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and mTORC2). mTORC1 controls cell growth, survival, and protein translation by regulating the phosphorylation of two major substrates: S6 kinase (S6K) and 4E-BP1. mTORC2 phosphorylates Akt at Serine 473 (S473), enhancing the catalytic activity of Akt, that has already been phosphorylated at Threonine 308 (T308). Thus, the mTOR complexes play an important role both upstream and downstream of Akt. Rapamycin and its analogs are allosteric mTOR inhibitors that bind FKBP12 and mTOR, and predominantly inhibit mTORC1. The rapamycin analog temsirolimus is approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma and the rapamycin analog everolimus is FDA approved for the treatment of pancreatic neuroendocrine tumors, renal cell carcinoma, sub-ependymal giant cell astrocytoma associated with tuberous sclerosis, as single agent therapy, and for the treatment of hormone-receptor positive breast cancer as combination therapy with exemestane. In spite of proven clinical benefit in breast cancer, objective responses remain rare. Thus there remains a need to identify predictors of response, optimal strategies for mTOR inhibition and rational combination therapies. There is emerging data on predictors of response to rapalog. Although preclinical studies suggest PIK3CA and PTEN alterations may confer sensitivity to rapalogs, the predictive value of these markers in the clinic has been controversial. Rare alterations such as mTOR activating mutations and TSC1 have been reported to confer sensitivity, while mTOR mutations in FKBP domain may confer rapalog resistance. The optimal strategy to target mTOR signaling is unknown. Preclinically, mTOR catalytic site inhibitors are more effective in cell lines with intrinsic or acquired rapamycin-resistance. The relative efficacy of other PI3K/Akt/mTOR inhibitors in breast cancer compared to rapalogs is not yet understood. Combinations with chemotherapy and other targeted agents are ongoing.
Citation Format: Funda Meric-Bernstam. Targeting mTOR for breast 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 IA22.
Abstract PR03: The Hippo pathway effector YAP1 contributes to escape from proliferation arrest under chronic PI3K/mTOR inhibition
Authors: Muranen Taru , Selfors Laura M. , Thoreen Carson C. , Gallegos Lisa L. , Coloff Jonathan L. , Mills Gordon B. , Brugge Joan S. 
Published: October 2015

Abstract
The PI3K/mTOR pathway is one of the most frequently mutated pathways in cancer. This pathway controls cell proliferation and cell survival, and represents an attractive target for cancer intervention. In animal tumor models, chronic treatment with PI3K/mTOR inhibitors initially induces tumor cytostasis. However, over time, tumor cells escape from drug-mediated proliferative suppression, resulting in relapse and tumor growth even in the presence of continued PI3K/mTOR inhibition. In this study we investigated the underlying molecular mechanisms that allow outgrowth of drug resistant tumor cells (“PI3K escapers”) after long-term treatment of tumor cell spheroids with PI3K/mTOR inhibitors. We identified several signaling pathways that were distinguishably altered in tumor cells that escaped proliferative suppression after chronic drug treatment compared to tumor cells acutely treated with inhibitor. Both MYC, which has been previously implicated in resistance to PI3K/mTOR inhibitors, and the Hippo pathway effector, YAP, were significantly upregulated in the “PI3K escapers” as well as multiple tumor cells lines that are resistant to PI3K/mTOR inhibition. Downregulation of either MYC or YAP abrogated the drug resistance. Although over-expression of MYC alone was sufficient to induce drug resistance, YAP was required for the MYC-induced resistant state, as knock-down of endogenous YAP resulted in loss of MYC-mediated resistance. Interestingly this resistance phenotype was associated with a KRAS or BRAF mutation, suggesting that MYC and YAP confer resistance in tumor cells in the context of ERK pathway activation. These data suggest that escape from proliferation suppression after chronic treatment with PI3K/mTOR in the context of activation of the KRAS pathway can be mediated by upregulation of MYC and YAP, which coordinately confer resistance.
This abstract is also being presented as Poster B41.
Citation Format: Taru Muranen, Laura M. Selfors, Carson C. Thoreen, Lisa L. Gallegos, Jonathan L. Coloff, Gordon B. Mills, Joan S. Brugge. The Hippo pathway effector YAP1 contributes to escape from proliferation arrest under chronic PI3K/mTOR inhibition. [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 PR03.
Abstract A16: Molecular tracking of metformin chemoprevention in a 300-person ALLIANCE randomized placebo controlled trial in women at high risk for triple-negative breast cancer
Authors: Seewaldt Victoria , Marshall James 
Published: October 2015

Abstract
Background: Metformin (1,1-dimethylbiguanide hydrochloride) is a well-tolerated biguanide currently undergoing testing for secondary breast cancer prevention in women with prior breast cancer. Recently published population studies suggest that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients. While metformin is one of the most extensively studied drugs in vitro and in vivo, many pre-clinical studies use concentrations of metformin that are &gt;1,000 times what is clinically achievable in humans and would be rapidly fatal if achieved. As a result, the molecular action of metformin in the breast tissue of women at high-risk who take metformin chemoprevention is poorly understood.
Methods/Results: Here we use combined proteomic profiling, breast tissue cytokine analysis, and in vivo analysis of live mammary epithelial cells for mitochondrial membrane and glucose uptake to track the molecular action of metformin chemoprevention in overweight and obese women at high-risk for triple-negative breast cancer. Women are enrolled in a 300 person ALLIANCE randomized, placebo controlled chemoprevention trial. Our studies to date have shown that overweight and obese women have activation of Akt/mTOR and IL6 /Stat3 epithelial activation, epithelial glucose uptake and increased mitochondrial membrane potential, and increased mammary tissue IL6/insulin.
Conclusion: These studies show our ability to directly track the molecular response to metformin chemoprevention.
Note: This abstract was not presented at the conference.
Citation Format: Victoria Seewaldt, James Marshall. Molecular tracking of metformin chemoprevention in a 300-person ALLIANCE randomized placebo controlled trial in women at high risk for triple-negative breast cancer. [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 A16.
Abstract A54: Possible targets of metformin in colorectal cancer
Authors: Sehdev Amikar , Khramtsova Galina , Joseph Nora , Polite Blase P. , Bissonnette Marc B. , Olufunmilayo Olopade I. 
Published: October 2015

Abstract
Background: Growing evidence suggests metformin improves survival in diabetic colorectal cancer (CRC) patients. However, the mechanism of action remains unclear. In order to explore the mechanistic relationship between metformin and colon cancer, we examined the expression levels of several proteins implicated in metformin's action.
Methods: We collected clinical-pathological and outcomes data on all CRC patients treated at the University of Chicago (UC) from 2006-2010. The data was collected through UC cancer registry and chart review. Diabetic CRC patients and matched controls (matched on race and stage) were selected for immunostaining (IHC). Tissues blocks (FFPE) were retrieved and tissue microarray (TMA) were constructed. IHC was performed for pAMPK, pmTOR, p70S6K, 4E-BP1, pAKT, IGF1R, beta-Catenin and Ki-67. Total score was calculated from the intensity and percentage scoring. The results were analyzed in two groups: diabetic CRC patients on metformin (group 1) and diabetic or non-diabetic CRC patients not on metformin (group 2). Chi-square test was done for estimating statistical significance between groups keeping a level of significance at 10% (alpha &lt; 0.10).
Results: The mean age of CRC patients was 62.7 years, 49% were males. Out of a total of 700 patients, 79 (11.21%) were diabetic. Metformin was prescribed to 40.5% of diabetic patients. Only 52 diabetics have FFPE block available so TMA was constructed with 104 patients in total (52 cases and 52 controls). Immunostaining was analyzable for a total of 84 patients. There were 18 and 66 patients in group 1 and 2, respectively. We found a lower expression of Ki-67 in the metformin group (group 1; 39%) as compared to non-metformin group (group 2; 64%) which was statistically significant (p = 0.04). IGF1R and beta-Catenin showed a higher expression in non-metformin group (89% and 95%, respectively) as compared to metformin group (72% and 83%, respectively) which was close to significance (p=0.12 and p=0.13, respectively). There was no significant difference between the expression of pAMPK, pmTOR, p70S6K, 4E-BP1 and pAKT in the two groups.
Conclusions: Metformin appears to improve the survival of CRC patients by decreasing proliferation. The results need to be validated in a larger study.
Citation Format: Amikar Sehdev, Galina Khramtsova, Nora Joseph, Blase P. Polite, Marc B. Bissonnette, Olopade I. Olufunmilayo. Possible targets of metformin in colorectal cancer. [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 A54.