Inositol Phospholipid Signaling in Physiology and Disease

Inositol Phospholipid Signaling in Physiology and Disease

Tuesday, June 26, 2012 - Wednesday, June 27, 2012

The New York Academy of Sciences

Presented By

Presented by the New York Academy of Sciences

 

Inositol phospholipid (IP) species are membrane-bound signaling molecules that have been implicated in almost all aspects of cellular physiology, including cellular growth, metabolism, proliferation, and survival. Therefore it is not surprising that disruptions within this key signaling pathway have been linked to conditions as diverse as cancer, inflammatory disease, obesity and diabetes. This 2-day conference will bridge the divide between basic and clinical research in different therapeutic areas by convening investigators working on the specificity and interplay of diverse IP-modifying enzymes (e.g. PI3K, PTEN, SHIP1/2 and INPP4A/B) in the context of both normal physiology and disease. Participants will then build on this foundation of knowledge to explore the latest therapeutic approaches for targeting this pathway through emerging methods of pharmaceutical modulation.

Keynote Speaker

Lewis C. Cantley, PhD

Harvard Medical School

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Agenda

* Presentation times are subject to change.


Day 1 – Tuesday, June 26, 2012

 

8:00 AM

Registration, Breakfast, and Poster Set-up

8:45 AM

Welcome and Introductory Remarks
Brooke Grindlinger, PhD, New York Academy of Sciences
William G. Kerr, PhD, SUNY Upstate Medical University

KEYNOTE LECTURE

9:00 AM

Phosphoinositol Signaling and Disease
Lewis C. Cantley, PhD, Beth Israel Deaconess Medical Center & Harvard University

SESSION I: Contribution of Inositol Phospholipid Signaling to Oncogenesis

Session Chair: Christina A. Mitchell, PhD, Monash University

10:00 AM

Characterization of INPP4B Tumor Suppressor Activity
Christina A. Mitchell, PhD, Monash University, Australia

10:30 AM

High-Frequency Mutation of the PI3K Signaling Suite in T-ALL
A. Thomas Look, MD, Dana Farber Cancer Institute

11:00 AM

Networking Coffee Break

11:30 AM

Glioma Formation, Cancer Stem Cells and PI3K/Akt Signaling
Eric C. Holland, MD, PhD, Memorial Sloan-Kettering Cancer Center

12:00 PM

Coordinate Tumor Suppressor Activities of Inositol Phosphatases PTEN and SHIP1 in B Cells
Robert C. Rickert, PhD, Sanford-Burnham Medical Research Institute

12:30 PM

PTEN Activity
Lloyd C. Trotman, PhD, Cold Spring Harbor Laboratories

1:00 PM

Networking Lunch & Poster Viewing

SESSION II: Pharmaceutical Modulation of Inositol Phospholipid Signaling in Cancer 

Session Chair: Langdon L. Miller, MD, Gilead Sciences

2:30 PM

Targeting PI3Kdelta in Lymphoid Malignancies
Langdon L. Miller, MD, Gilead Sciences

3:00 PM

Challenges in the Clinical Development of PI3-Kinase Inhibitors for the Treatment of Solid Tumors
Cristian Massacesi, MD, Novartis Pharmaceuticals

3:30 PM

Mechanisms of PI3K Inhibition in Cancer
Neal Rosen, MD, PhD, Memorial Sloan-Kettering Cancer Center

4:00 PM

Interrupting the PI3K-AKT-mTOR Pathway in Cancer Therapy
David B. Solit, MD, Memorial Sloan-Kettering Cancer Center

4:30 PM

Networking Coffee Break

PANEL DISCUSSION

5:00 PM

What Inositol Phospholipid Species Are Required for Malignant Transformation?
Moderator: William G. Kerr, PhD, SUNY Upstate Medical University

Panelists:
Lewis C. Cantley, PhD, Beth Israel Deaconess Medical Center & Harvard University
Langdon L. Miller, MD, Gilead Sciences
Christina A. Mitchell, PhD, Monash University
Robert Rickert, PhD, Sanford-Burnham Medical Research Institute

6:00 PM

Poster Session and Conference Reception

7:30 PM

Day 1 Concludes

Day 2 – Wednesday, June 27, 2012

8:00 AM

Breakfast

SESSION III: Young Investigator Presentations

Session Chairs: Christina A. Mitchell, PhD, Monash University, Australia & William G. Kerr, PhD, SUNY Upstate Medical University

9:00 AM

Inactivation of P110delta PI3-Kinase Unlocks Anti-Cancer Immune Responses
Khaled Ali, PhD, Queen Mary University of London, United Kingdom

9:15 AM

PI3K-AKT-mTORC1-S6K1/2 Axis Controls Th17 Differentiation
Shigenori Nagai, PhD, Keio University School of Medicine, Japan

9:30 AM

Osteolineage Expression of SHIP1 is Required for Bone Marrow Microenvironment Signaling
Sonia Iyer, SUNY Upstate Medical Center

9:45 AM

Class III PI3K Vps34 Plays an Essential Role in Autophagy, Endocytosis, and Heart and Liver Function
Nadia Jaber, Stony Brook University

10:00 AM

Networking Coffee Break

SESSION IV: Modulation of Inositol Phospholipid Signaling in Immune Function 

Session Chair: David A. Fruman, PhD, University of California, Irvine

10:30 AM

PI3K p110delta in T Cell Immunity and Inflammation
Klaus Okkenhaug, PhD, Babraham Institute, United Kingdom

11:00 AM

mTOR Kinase Inhibitors Impact B Cell Function Through the AKT-FOXO Axis
David A. Fruman, PhD, University of California, Irvine

11:30 AM

Role of SHIP in Inflammation at Mucosal Surfaces
William G. Kerr, PhD, SUNY Upstate Medical University

12:00 PM

Control of T Cell Homeostasis and Responses by PTEN
Laurence Turka, MD, Beth Israel Deaconess Medical Center & Harvard Medical Center

12:30 PM

Networking Lunch

SESSION V: Modulation of Inositol Phospholipid Signaling in Inflammatory Disease 

Session Chair: Vito J. Palombella, PhD, Infinity Pharmaceuticals, Inc.

1:30 PM

Targeting PI3Kgamma & PI3Kdelta in Inflammation
Vito J. Palombella, PhD, Infinity Pharmaceuticals, Inc.

2:00 PM

AQX-1125: A Novel Allosteric Activator of SHIP1. From Preclinical Studies to Proof-of-Concept Clinical Studies
David Chernoff, MD, Aquinox Pharmaceuticals, Inc.

2:30 PM

PI3Kdelta Inhibition: A Future Paradigm Change for the Inhaled Therapy of Respiratory Diseases?
Augustin Amour, PhD, GlaxoSmithKline

3:00 PM

PI3Kgamma Inactivation in Inflammation and Autoimmune Disease
Wai-Ping Fung-Leung, PhD, Janssen Research & Development, LLC

3:30 PM

Networking Coffee Break

SESSION VI: Inositol Phospholipid Signaling and Metabolic Disease 

Session Chair: Matthias P. Wymann, PhD, University of Basel, Switzerland

4:00 PM

PI3Kgamma Signaling – Gateway to Inflammation and Obesity
Matthias P. Wymann, PhD, University of Basel, Switzerland

4:30 PM

The Role of Lipid Kinases/Phosphatase Signaling in the Hypothalamus and Metabolic Disease
Jens C. Brüning, MD, University of Cologne & MPI for Neurological Research, Germany

5:00 PM

Phospholipase D Signaling in Diabetes and Cardiovascular Disease
Michael A. Frohman, MD, PhD, Stony Brook University

5:30 PM

INPP4B, A Modulator of Osteoclast Differentiation
Jean Vacher, PhD, Clinical Research Institute of Montreal, Canada

6:00 PM

Closing Remarks
William G. Kerr, PhD, SUNY Upstate Medical University

7:00 PM

Conference Concludes

Speakers

Organizers

William G. Kerr, PhD

SUNY Upstate Medical University

Christina A. Mitchell, PhD

Monash University

Christian Rommel, PhD

Intellikine

Keynote Speaker

Lewis C. Cantley, PhD

Beth Israel Deaconess Medical Center & Harvard University

Speakers

Khaled Ali, PhD

Queen Mary University of London, United Kingdom

Augustin Amour, PhD

GlaxoSmithKline

Jens C. Brüning, MD

University of Cologne & MPI for Neurological Research, Germany

David Chernoff, MD

Aquinox Pharmaceuticals

Michael A. Frohman, MD, PhD

Stony Brook University

David A. Fruman, PhD

University of California, Irvine

Wai-Ping Fung-Leung, PhD

Johnson & Johnson Pharmaceuticals

Eric C. Holland, MD, PhD

Memorial Sloan-Kettering Cancer Center

Sonia Iyer

SUNY Upstate Medical Center

Nadia Jaber

Stony Brook University

William G. Kerr, PhD

SUNY Upstate Medical University

A. Thomas Look, MD

Dana Farber Cancer Institute

Cristian Massacesi, MD

Novartis Pharmaceuticals

Langdon L. Miller, MD

Gilead Sciences, Inc.

Christina A. Mitchell, PhD

Monash University

Shigenori Nagai, PhD

Keio University School of Medicine, Japan

Klaus Okkenhaug, PhD

Babraham Institute, UK

Vito Palombella, PhD

Infinity Pharmaceuticals, Inc.

Robert C. Rickert, PhD

Sanford-Burnham Medical Research Institute

Neal Rosen, MD, PhD

Memorial Sloan-Kettering Cancer Center

David B. Solit, MD

Memorial Sloan-Kettering Cancer Center

Lloyd C. Trotman, PhD

Cold Spring Harbor Laboratories

Laurence Turka, MD

Beth Israel Deaconess Medical Center

Jean Vacher, PhD

Clinical Research Institute of Montreal, Canada

Matthias P. Wymann, PhD

University of Basel, Switzerland

*Check the conference website regularly for updates.

Abstracts

Day 1: Tuesday, June 26, 2012

Keynote Lecture 1

Phosphoinositol Signaling and Disease
Lewis C. Cantley, PhD, Harvard University Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA

Phosphoinositide 3-Kinase (PI3K) is a central enzyme in a signaling pathway that mediates cellular responses to growth factors. This enzyme phosphorylates the 3 position of phosphatidylinositol-4,5-bisphosphate to produce phosphatidylinositol-3,4,5-trisphosphate (PIP3) at the plasma membrane. A number of signaling proteins, including the Ser/Thr protein kinases, AKT and PDK1, contain pleckstrin homology domains that bind specifically to PIP3. Thus, the generation of PIP3 at the plasma membrane in response to activation of PI3K by growth factors results in the initiation of downstream Ser/Thr phosphorylation cascades that control a variety of cellular responses. The signaling pathway downstream of PI3K 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. Based on deletion of genes encoding the catalytic or regulatory subunits of PI3K in the mouse, PI3K mediates insulin dependent regulation of glucose metabolism, and defects in activation of this pathway result in insulin resistance. In contrast, mutational events that lead to hyperactivation of the PI3K pathway result in cancers. 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. We have generated mouse models in which a mutated form of the PIK3CA gene is expressed in a tissue specific and reversibly inducible manner. These mice develop cancers that are dependent on continuous expression of the mutant PIK3CA gene. The PIK3CA driven tumors are FDG-PET positive and turning off PI 3-Kinase with PI3K inhibitors that are in human clinical trials results in an acute decline in FDG-PET signal that precedes tumor shrinkage. These results suggest that the ability of PI3K to stimulate high rates of glucose uptake and metabolism may be critical for the survival of PIK3CA mutant tumors. The role of PI3K inhibitors for treating cancers in mouse models and in human trials will be discussed.
 

Session I: Contribution of Inositol Phospholipid Signaling to Oncogenesis

Characterisation of INPP4B Tumor Suppressor Activity
Christina Mitchell, PhD, Monash University

Phosphoinositide 3-kinase generates PtdIns(3,4,5)P3 at the plasma membrane, which is rapidly dephosphorylated either by PTEN (phosphatase and tensin homologue deleted on chromosome 10) to PtdIns(4,5)P2, or by the inositol polyphosphate 5-phosphatases, generating PtdIns(3,4)P2.The inositol polyphosphate 4-phosphatases, INPP4A and INPP4B degrade PtdIns(3,4)P2 to PtdIns(3)P and respectively regulate neuroexcitatory cell death, or act as a tumour suppressor in breast, prostate and other cancers. INPP4B loss of heterozygosity (LOH) and loss of expression of INPP4B protein has been identified in specific breast cancer subtypes, suggesting INPP4B acts as a tumour suppressor. INPP4B is expressed in nonproliferative estrogen receptor (ER)-positive cells in the normal breast and INPP4B knockdown in ER-positive breast cancer cells increases Akt activation, cell proliferation, and xenograft tumour growth. INPP4B protein expression is lost most commonly in aggressive basal-like breast carcinomas and its loss is frequently associated with PTEN-null tumours. INPP4B is expressed in benign prostatic tissue and in prostate cancers INPP4B protein expression is often reduced or lost. We have examined the molecular regulation of INPP4B enzyme activity and have identified INPP4B acts as an allosteric enzyme in its degradation of PtdIns(3,4)P2. These studies reveal INPP4B enzyme activity is regulated by both protein:protein interactions and intramolecular interactions with other phosphoinositides.
 

Coauthors: N.K. Rynkiewicz1, H.J. Liu1, L.M. Ooms1, C.G. Fedele1, C.A. McLean2, C. A Mitchell1
1 Department of Biochemistry, Monash University, Melbourne, Australia
2Department of Anatomical Pathology, Alfred Hospital, Melbourne, Australia


 

High-Frequency Mutation of the PI3K Signaling Suite in T-ALL
Thomas Look, MD, Dana Farber Cancer Center

To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array CGH and sequence analysis. Alterations of PTEN, PI3K or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = 0.007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. To establish the role of PI3K signaling in T-ALL, we generated a 4-hydroxytamoxifen inducible zebrafish model of MYC-induced T-ALL, in which most tumors demonstrate dependence on the MYC oncoprotein. To test whether MYC addiction requires pten in vivo, MYC-ER transgenic zebrafish were mated to zebrafish harboring loss-of-function mutations in their pten genes, and offspring were raised in 4-hydroxytamoxifen. Pten haploinsufficiency impaired T-ALL regression upon MYC transgene downregulation, an effect that was phenocopied by expression of constitutively active Akt. Our findings suggest that Akt pathway activation is sufficient to maintain the transformed phenotype in T-ALL lymphoblasts, even after MYC transgene downregulation. These findings add significantly to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.
 

Coauthors: Alejandro Gutierrez,1,5 Takaomi Sanda,1 Donna Neuberg,2 Stuart S. Winter,7 Richard Larson,8 Jianhua Zhang,3 Alexei Protopopov,3 Lynda Chin,3,4 Pier Paolo Pandolfi,6 Lewis B. Silverman,1,5 Stephen P. Hunger,9 Stephen E. Sallan,1,5 and A. Thomas Look1,5
1Department of Pediatric Oncology
2Department of Biostatistics and Computational Biology
3Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science
4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
5Division of Hematology/Oncology, Children’s Hospital, Boston, MA
6Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Boston, MA
7Department of Pediatrics
8Department of Pathology, The University of New Mexico Health Sciences Center, Albuquerque, NM
9Center for Cancer and Blood Disorders, The Children’s Hospital and University of Colorado School of Medicine, Aurora, CO


 

Glioma Formation, Cancer Stem Cells and PI3K/Akt Signaling
Eric C. Holland, MD, PhD, Memorial Sloan-Kettering Cancer Center

Cells exist in brain tumors that have stem-cell characteristics including expression of markers, ability to grow as neurospheres, and enhanced ability to form tumors upon transplantation. One marker of stem-ness is the activity of the transmembrane ATP binding cassette protein ABCG2 which pumps small molecules out of the cytoplasm and can be identified by its ability to eflux florescent dye from the cell. This phenotype can be detected on FACS as cells excluding Hoechst dye and is called the side population (SP). SP analysis enriches for stem-like cells in many tumor types including gliomas. Stem-like cells are relatively resistant to therapy and maintenance of this character is driven by complex interactions of several pathways including PI3K, notch, and nitric oxide (NO).Notch signaling elevates ABCG2 mRNA while Akt activity translocates ABCG2 to the plasma membrane to be active. In medulloblastomas, radiation therapy spares cells in the perivascular niche (PVN). These PVN cells acquire increased stem-cell characteristics and elevated Akt activity in response to radiation, and Aktblockade reduces their survival. Cells with stem-cell character also occupy the glioma PVN. In these tumors, NO is produced from endothelial cellsvia eNOS. NO activates cGMP, PKG and notch in the cells surrounding blood vessels leading to the SP phenotype and other stem-cell characteristics. Finally, SP appears to be more than just a marker for stem-like cells. The activity of ABCG2 actively drives stem-cell characteristics although the substrate that it pumps to achieve this effect is currently unknown.
 

Coordinate Tumor Suppressor Activities of Inositol Phosphatases PTEN and SHIP1 in B Cells
Robert C. Rickert, PhD, Sanford-Burnham Medical Research Institute

PTEN and SHIP antagonize PI3K signaling by dephosphorylating PtdIns(3,4,5)P3. While PTEN is widely expressed and constitutively active, SHIP is hematopoietically-restricted and needs to be recruited to phosphorylated target receptors via an SH2-domain interaction. Both PTEN and SHIP are also targets of downregulation by microRNAs. We have shown that in the absence of PTEN, B cell transformation does not occur due to the retained function of SHIP. Here I will present new findings on the distinct roles of SHIP and PTEN in modulating PI3-kinase signaling in response to antigen receptor signaling as well as microenvironmental cues. These studies comment on the contributions of inflammation and homeostatic signaling to B lymphomagenesis.
 

PTEN Signaling in Prostate Cancer
Loyd Trotman, PhD, Cold Spring Harbor Laboratories

Session II: Pharmaceutical Modulation of Inositol Phospholipid Signaling in Cancer

Session Chair: Langdon M. Miller, MD, Gilead Sciences

Targeting PI3Kdelta in Lymphoid Malignancies
Langdon L. Miller, MD, Gilead Sciences, Inc.

The PI3K signaling pathway has emerged as a promising therapeutic target in cancer and inflammatory disorders. Among several forms of the PI3K enzyme is PI3K-delta, which is expressed in lymphocytes, other immune cells, and in various tumor types. Genetic and pharmacological approaches have established an important role for PI3K-delta in immune cell function, mast cell degranulation, and leukocyte migration. PI3K-delta has been shown to integrate signaling from cell surface receptors that promote malignant B-cell proliferation, migration, and survival. GS-1101 (also known as CAL-101) is a novel drug that selectively inhibits PI3K-delta activity. In preclinical efficacy pharmacology studies evaluating lymphoid tumors, GS-1101 has reduced PI3K-delta signaling, interrupted cell cycling, and enhanced apoptosis. GS-1101 has been evaluated in clinical studies in patients with lymphoid malignancies, including indolent NHL, mantle cell lymphoma, and chronic lymphocytic leukemia. Among patients with these cancers, substantial antineoplastic activity has been observed; GS-1101 has induced durable tumor regressions in the majority of patients. Thus, initial characterization of PI3K delta has allowed development of GS-1101 as the first drug to therapeutically modulate this important enzyme. In turn, the early success of GS-1101 is setting the stage for further examination of the role of PI3K-delta in health and disease.
 

Challenges in the Clinical Development of PI3 Kinase Inhibitors for the Treatment of Solid Tumors
Cristian Massacesi, MD, Novartis Pharmaceuticals, France

Multiple components of the PI3K pathway are often dysregulated in cancer cells and over-activation of PI3K signaling is implicated in many aspects of tumor growth and survival. Activation of this pathway can be the result of: i) Amplification and/or overexpression of the p110α catalytic subunit; ii) Presence of activating mutations in the PIK3CA gene encoding the p110α catalytic subunit; iii) Constitutively active mutants or overexpression of receptor tyrosine kinases (e.g. EGFR, ErbB2) leading to constitutive recruitment and activation of PI3K; iv) Constitutive recruitment and activation by mutant forms of the Ras oncogene; v) Loss or inactivating mutation of the tumor suppressor gene PTEN, a endogenous negative regulator of the PI3K pathway; or vi) Overexpression of the downstream kinase Akt.
 
Preclinical work suggests that inhibition of the PI3K signaling pathway might provide benefit for the treatment of many solid tumors such as breast cancer, prostate cancer, glioblastoma multiforme, colon cancer, lung cancer, etc. Therefore, therapeutic interventions on PI3K signaling could represent a rationale approach for the treatment of many tumors and could, in addition, increase the efficacy of already established antineoplastic treatments like cytotoxic agents, endocrine agents, targeted agents, etc.
 
Currently a large number of PI3K and Akt inhibitors are being investigated in clinical trials. Despite strong scientific rationale and supportive preclinical data, a consistent marginal single agent clinical activity has been reported to date for most of these compounds, across different tumor types. Nevertheless, interesting preliminary clinical data are emerging when this class of compounds are combined with other antineoplastic agents (eg, with hormonal agents in breast cancer or with chemotherapy in NSCLC), These emerging data suggest that targeting the overactivated PI3K pathway may be critical to overcome drug-resistance and may provide clinical benefit.
 
With regards to biomarker strategy, the complexity of PI3K/Akt pathway and the high number of key players in the pathway has thus far limited the profiling of biomarkers which can guide the pre-identification of patients most likely to benefit from PI3K inhibition.
 
An overview on the challenges faced in the clinical development of PI3K inhibitors will be discussed using Novartis compounds as example.
 

Mechanisms of PI3K Inhibition in Cancer
Neal Rosen, MD, PhD, Memorial Sloan-Kettering Cancer Center

Interrupting the PI3K-AKT-mTOR Pathway in Cancer Therapy
David B. Solit, MD, Memorial Sloan-Kettering Cancer Center

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