Cancer Cell Metabolism: Unique Features Inform New Therapeutic Opportunities

Cancer Cell Metabolism: Unique Features Inform New Therapeutic Opportunities

Thursday, May 28, 2015

The New York Academy of Sciences

Presented By

 

There has been a resurgence of interest in understanding how metabolic pathways are altered in cancer and how these alterations can be exploited for therapeutic gain. However, because normal cells and cancer cells often require the same energy sources and metabolic pathways, designing metabolism-based cancer therapies without systemic toxicity has proven challenging. The goal of this meeting is to bring experts together to discuss recent findings suggesting that discrete metabolic pathways and activities are over-utilized in certain cancer contexts, leaving cancer cells selectively vulnerable to specific metabolic interventions. This symposium will highlight insights into tumor metabolism from leaders in the field and explore how this information is being used to design safe and effective, metabolism-targeted therapies.

*Reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

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Agenda

* Presentation titles and times are subject to change.


May 28, 2015

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome and Introductory Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Lydia Finley, PhD, Memorial Sloan-Kettering Cancer Center

8:45 AM

Keynote Lecture - Beyond Glucose and Glutamine: Some Cancer Cells Forage for Food
Craig B. Thompson, MD, Memorial Sloan-Kettering Cancer Center

9:25 AM

mTOR, Cancer Metabolism and Therapeutic Opportunities
John Blenis, PhD, Weill Cornell Medical College

9:55 AM

Mitochondrial Amino Acid Metabolism and Nutrient Sensing
Christian Metallo, PhD, University of California, San Diego

10:25 AM

Coffee Break

10:55 AM

Role of Metabolism in Supporting Cell Proliferation
Matthew G. Vander Heiden, MD, PhD, Massachusetts Institute of Technology

* The 10:55 am talk will not be broadcast as part of the live webinar.

11:25 AM

Metabolic Regulation of Cell Fate Decisions
Lydia Finley, PhD, Memorial Sloan-Kettering Cancer Center

11:45 AM

Networking Lunch

12:45 PM

A Post-transcriptionally Regulated Metabolic Pathway that enables Liver Metastatic Colonization by Colon Cancer
Sohail Tavazoie, MD, PhD, The Rockefeller University

1:15 PM

Reversible Metabolic Changes in Human Melanoma Cells Enable Distant Metastasis
Elena Piskounova, PhD, University of Texas Southwestern Medical Center

1:35 PM

Identifying Metabolic Dependencies in Pancreatic Cancer
Alec Kimmelman, MD, PhD, Harvard Medical School

2:05 PM

Cell Cycle Control of Cancer Cell Metabolism
Selina Chen-Kiang, PhD, Weill Cornell Medical College

* The 2:05 pm talk will not be broadcast as part of the live webinar.

2:35 PM

Closing Remarks
Costas Andreas Lyssiotis, PhD, Weill Cornell Medical College

2:50 PM

Networking Reception

4:00 PM

Adjourn

Speakers

Organizers

Lydia Finley, PhD

Memorial Sloan-Kettering Cancer Center

Lydia Finley is the Jack Sorrell Fellow of the Damon Runyon Cancer Research Foundation and a postdoctoral fellow in the laboratory of Craig Thompson at Memorial Sloan Kettering Cancer Center. She earned her Ph.D. in the laboratory of Marcia Haigis at Harvard Medical School. Her research focuses on understanding how signaling events regulate intracellular metabolic pathways and how metabolites influence chromatin state and cell fate decisions.

Steven S. Gross, PhD

Weill Cornell Medical College

Steven S. Gross is Professor of Pharmacology, Director of the Center for Excellence in Life Sciences Mass Spectrometry and Director of Advanced Training in Pharmacology at the Weill Cornell Medical College. His primary research interest is in cell–cell communication, with a focus on nitric oxide (NO) and reactive molecules as mediators of cell signaling. In the late 1980s, Dr Gross and colleagues made the initial identification of L-arginine as the precursor of NO in blood vessels. They were also first to establish that NOS inhibition elevates blood pressure in animals, demonstrating that NO plays a physiological role in controlling blood pressure and vascular tone. Since then, research efforts have been directed toward elucidating the enzymes and mechanisms that regulate NO synthesis in cells. His basic studies have provided fundamental insights into the therapeutic control of NO synthesis, resulting in core technologies for the creation of ArgiNOx Inc., a biotech start-up that seeks to develop novel NO-based drugs. He is a founder and Board Director of the Nitric Oxide Society and Co-Chairs the Steering Committee of the Biomedical Pharmacology Discussion Group (BPDG) at NYAS. Dr Gross received his PhD in Biomedical Science from the Mount Sinai School of Medicine in New York City.

Costas Andreas Lyssiotis, PhD

Weill Cornell Medical College

Dr. Lyssiotis is an Assistant Professor at the University of Michigan Medical School with appointments in the Departments of Physiology and Medicine. His lab studies the biochemical pathways and metabolic requirements that enable tumor survival and growth and, in particular, how this information can be used to design targeted therapies. Among his many contributions, Dr. Lyssiotis demonstrated that pancreatic cancers are addicted to glucose and glutamine and use these nutrients in previously undescribed pathways to make DNA and to generate free radical-combating antioxidants, respectively. For this work, he has been awarded a Pathway to Leadership Grant from the Pancreatic Cancer Action Network, the Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation and the Tri-Institutional Breakout Prize for Junior Investigators.

Sonya Dougal, PhD

The New York Academy of Sciences

Keynote Speaker

Craig B. Thompson, MD

Memorial Sloan-Kettering Cancer Center

Craig B. Thompson, MD is the President and Chief Executive Officer of Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Thompson is a board-certified internist and medical oncologist with extensive research experience in cancer, immunology, and translational medicine. His current research focuses on the regulation of cellular metabolism during cell growth/differentiation and on the role that metabolic changes play in the origin and progression of cancer. Dr. Thompson is a member of the Institute of Medicine, the National Academy of Sciences, the American Academy of Arts and Sciences, and the Medical Advisory Board of the Howard Hughes Medical Institute.

Speakers

John Blenis, PhD

Weill Cornell Medical College

Dr. John Blenis is the Anna-Maria and Stephen Kellen Professor of Cancer Research and Professor of Pharmacology at Weill Cornell Medical College. He completed his B.A. degree (1977) at the University of California, Berkeley, USA, his Ph.D. (1983) at Michigan State University, Michigan, USA, and his postdoctoral research at Harvard University, Cambridge, Massachusetts, USA (1983-1987).  Dr. Blenis was an Assistant Professor at Northwestern University (1987-1989), and then Assistant, Associate and Tenured Professor of Cell Biology from 1989-2014 at Harvard Medical School before moving his laboratory to the Meyer Cancer Center at Weill Cornell Medical College. The major objectives of his research are to define and characterize the molecular basis of cellular signaling with a focus on the Ras-ERK-RSK and PI3K-mTOR-S6K1 pathways, and how these signaling systems contribute to the normal and disease-associated physiology with a focus on cancer.  These studies have and continue to reveal several current and future therapeutic targets and biomarkers for cancer therapy.

Selina Chen-Kiang, PhD

Weill Cornell Medical College

Selina Chen-Kiang, PhD, is Professor of Pathology and Professor of Immunology and Microbial Pathogenesis at the Weill Cornell Medical College. She obtained her PhD in Human Genetics and Development from Columbia University and completed post-doctoral training in molecular biology at The Rockefeller University. Her work focuses on cell cycle control of B cell immunity and malignancies. She pioneered the concept of reprogramming cancer cells by cell cycle control, which has led to the development of the first mechanism-based combination cell cycle therapy in human cancer by her team. Her current interests include cell cycle control of therapeutic targeting of PI3K and BTK, as well as metabolism and drug resistance in lymphoma and myeloma. Dr. Chen- Kiang has served on various advisory boards and is the recipient of many awards, including an Inaugural Specialized Center for Research Award in myeloma and the Researcher of the Year Award from the Leukemia and Lymphoma Society.

Lydia Finley, PhD

Memorial Sloan-Kettering Cancer Center

Lydia Finley is the Jack Sorrell Fellow of the Damon Runyon Cancer Research Foundation and a postdoctoral fellow in the laboratory of Craig Thompson at Memorial Sloan Kettering Cancer Center. She earned her Ph.D. in the laboratory of Marcia Haigis at Harvard Medical School. Her research focuses on understanding how signaling events regulate intracellular metabolic pathways and how metabolites influence chromatin state and cell fate decisions.

Alec Kimmelman, MD, PhD

Harvard Medical School

Dr. Kimmelman is currently an Associate Professor of Radiation Oncology at the Dana-Farber Cancer Institute at Harvard Medical School. He completed his undergraduate education at Cornell University and received his MD/PhD from the Mount Sinai School of Medicine in NY. After graduating, he completed residency training at the Harvard Radiation Oncology Program and performed his post-doctoral studies in the laboratory of Ronald A. DePinho at the Dana-Farber Cancer Institute where he identified novel genes that are important in the invasive and metastatic phenotype of pancreatic cancer. Dr. Kimmelman has been studying Ras oncogenes for more than 15 years. His lab is focused on pancreatic cancer and his recent work involves the study of the Kras-dependent deregulation of metabolic pathways in the disease and its relation to therapeutic resistance. Indeed, the Kimmelman lab has been at the forefront of defining the metabolic landscape of pancreatic cancer. His group first identified that pancreatic cancers require Kras for tumor maintenance through its control of cellular metabolism. Additionally, their work has uncovered that pancreatic cancers are addicted to autophagy for continued growth and this has motivated the development of multiple clinical trials, including two clinical trials at the Dana-Farber Harvard Cancer Center for the treatment of pancreatic cancer patients. Dr. Kimmelman is also currently an attending Radiation Oncologist at the Dana-Farber Cancer Institute and Brigham and Womens Hospital specializing in Gastrointestinal Malignancies and is the Director of Preclinical Therapeutics of the small animal microirradiator facility. Dr. Kimmelman is the recipient of many prestigious awards, including the Ruth Leff Siegal Award from Columbia University for excellence in pancreatic cancer research.

Christian Metallo, PhD

University of California, San Diego

Christian Metallo joined the University of California, San Diego in 2011 and is currently an assistant professor in the Department of Bioengineering. He received his bachelor’s in chemical engineering from the University of Pennsylvania in 2000 before joining Merck Research Laboratories to conduct bioprocess engineering research.  He received his PhD from the University of Wisconsin-Madison Department of Chemical and Biological Engineering in 2008 and was an American Cancer Society Postdoctoral Fellow in Chemical Engineering at the Massachusetts Institute of Technology.  Christian was the recipient of the Biomedical Engineering Society Rita Schaffer Young Investigator Award in 2012 and is a 2013 Searle Scholar.

Elena Piskounova , PhD

University of Texas Southwestern Medical Center

Dr. Elena Piskounova is a Helen Hay Whitney Fellow in the laboratory of Dr. Sean J Morrison at Children’s Research Institute, University of Texas Southwestern Medical Center. Her research is focused on understanding the metabolic requirements and adaptations that occur in cancer cells during distinct steps of the metastatic cascade, using a clinically relevant model of melanoma. Through this work, she aims to uncover and validate novel therapeutic targets specific for metastatic disease. Prior to joining the Morrison lab, Dr. Piskounova completed her PhD in Biological and Biomedical Sciences at Harvard Medical School in Boston, MA, where she studied the molecular mechanisms that mediated posttranscriptional processing of the let-7 family of microRNAs by the Lin28 oncoproteins.  She obtained her bachelor’s and master’s degrees in Molecular and Cellular Biochemistry from the University of Oxford, UK.

Sohail Tavazoie, MD, PhD

The Rockefeller University

Dr. Tavazoie received his undergraduate degree from the University of California, Berkeley, his PhD from Harvard University and his MD from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology. Following a residency and internship in internal medicine at Harvard’s Brigham and Women’s Hospital, he joined Memorial Sloan Kettering Cancer Center as a clinical fellow in 2005 and became a research fellow in medical oncology in 2006. He joined Rockefeller as an assistant professor in 2009 and was named associate professor in 2015. In 2009, Dr. Tavazoie was the recipient of the NIH Director’s New Innovator Award and a combined American Society of Clinical Oncology and American Association for Cancer Research Young Investigator Award. He was also named a Rita Allen Foundation Scholar, a Sidney Kimmel Foundation for Cancer Research Scholar and a Department of Defense Era of Hope Scholar. Dr. Tavazoie was elected to the American Society for Clinical Investigation and is an attending medical oncologist at Memorial Sloan Kettering Cancer Center.

Matthew G. Vander Heiden, MD, PhD

Massachusetts Institute of Technology

Matthew Vander Heiden is the Eisen and Chang Associate Professor in the Koch Institute for Integrative Cancer Research and the Department of Biology at the Massachusetts Institute of Technology. He is also an Instructor of Medicine at the Dana-Farber Cancer Institute and Harvard Medical School. Dr. Vander Heiden received his MD and PhD degree from the University of Chicago. He also completed clinical training in Internal Medicine and Medical Oncology at the Brigham and Women’s Hospital / Dana-Farber Cancer Institute prior to completing a post-doctoral fellowship at Harvard Medical School.

Abstracts

Beyond Glucose and Glutamine: Some Cancer Cells Forage for Food
Craig B. Thompson, Memorial Sloan-Kettering Cancer Center, New York, NY

Under conditions of an abundant supply of extracellular glucose and glutamine, cancer cells synthesize lipids, nucleic acids, and non-essential amino acids from these precursors. However, when cancer grows to exceed its vascular supply, cells must adapt to lower availability of essential nutrients and oxygen. In the past year, we have seen a major breakthrough in the discovery of novel mechanisms by which cancer cells adapt to metabolic stress. It was previously determined that glutamine-dependent lipid synthesis could support de novo lipid synthesis under hypoxia but metabolic tracing studies uncovered that over 50% of lipids used in phospholipid biosynthesis in hypoxic cells come from exogenous sources. We were able to determine that hypoxia-induced macropinocytosis facilitates the uptake and incorporation of unsaturated phospholipids to maintain effective unsaturated lipid levels under conditions in which stearoyl-CoA desaturase is inhibited by oxygen limitation. Follow up studies have demonstrated that this property of cellular scavenging of extracellular macromolecules is induced in a Ras-dependent fashion in transformed cells and provides a potent mechanism by which Ras-transformed cells can adapt to metabolic stress in their environment. This pathway of cellular acquisition of bioenergetic substrates has previously escaped detection because, in complete medium, the utilization of macropinocytosed proteins as metabolic substrates is actively suppressed. The molecular details of this suppression and the implication of these studies to understanding both cancer and wound repair will be discussed.
 

mTOR, Cancer Metabolism and Therapeutic Opportunities
John Blenis, PhD1

The mTOR Complex 1 (mTORC1) signaling pathway has evolved to sense and respond to cellular energy status, nutrient availability and surrounding oxygen concentrations.  In addition, mTORC1 can be further activated by mitogen- and hormone-stimulated kinases including Akt, ERK and RSK, and suppressed by mTORC1-regulated S6K1 via a variety of negative feedback loops.  The integration of these multiple inputs control the strength and duration of downstream signaling, which is important in differentially regulating mTORC1-dependent processes such as protein synthesis and cellular metabolism.  I will discuss how mTORC1 and S6K1 regulate aspects of nutrient metabolism, mRNA metabolism and protein production; biological processes critical to the control of cell growth while at the same time creating vulnerabilities that may provide important therapeutic opportunities in cancers with activated mTORC1 signaling.
 
Coauthors: Sang Gyun Kim, PhD1, Sanguine Byun, PhD2, Jing Li, PhD1, Andy Choo, PhD1, Alfredo Csibi, PhD1, Gina Lee, PhD1, Sam Lee, PhD2
1 Sandra and Edward Meyer Cancer Center, Department of Pharmacology, Belfer Research Building, Weill Cornell Medical College, New York, NY
2 Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA

 

Mitochondrial Amino Acid Metabolism and Nutrient Sensing
Christian Metallo, PhD, University of California, San Diego

Metabolism is central to virtually all cellular functions and contributes to a range of diseases. A detailed understanding of how biochemical pathways are regulated is necessary to understand and control cell function. Quantitative information describing the flow of metabolites through biochemical networks provides critical insights into how different nutrients contribute to energy metabolism and biosynthesis. To this end we apply stable isotope tracers, mass spectrometry, and metabolic flux analysis (MFA) to study central metabolism in mammalian cells. Using these approaches we have characterized how proliferating and differentiated adipocytes regulate flux of glucose and essential amino acids into mitochondria for biosynthesis of fatty acids and glutamine. Through this analysis we have also identified fatty acids synthesized by adipocytes that integrate carbohydrate, fatty acid, and protein availability. The abundance of these metabolites changes in response to changes in diet or cellular microenvironments and influences metabolic signaling pathways. Ultimately, the application of MFA to these cellular models has improved our ability to characterize intracellular metabolic processes, providing a mechanistic understanding of cellular physiology and metabolic function.
 

Role of Metabolism in Supporting Cell Proliferation
Matthew G. Vander Heiden, MD, PhD, Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA, USA

Cells adapt metabolism to meet distinct physiological needs, and metabolic regulation influences tumor progression. To proliferate, cancer cells must adapt metabolism to support anabolic processes and allow the accumulation of biomass. However, those nutrients with the highest consumption by cancer cells are not necessarily the fuels that contribute directly to cell mass. Cell culture provides a system to study how metabolism supports proliferation, but understanding non-proliferating cell populations requires an analysis of metabolism in patients and in tumor tissue. Use of mass spectrometry to trace nutrient use both in cell culture models and mouse cancer models suggests that both glucose and serine metabolism are critical to support nucleotide synthesis. Regulation of these pathways determines whether sufficient nucleotides are available to support cell proliferation and begins to clarify how metabolism is regulated to control cell proliferation.
 

Metabolic Regulation of Cell Fate Decisions
Lydia W.S. Finley, PhD1

The deposition and removal of DNA and histone modifications depends on the availability of specific metabolites, suggesting that cellular metabolic pathways may tightly regulate chromatin modifications and gene expression. However, whether changes in metabolic flux can influence cell state is poorly understood. Here we show that mouse embryonic stem cells (ESCs) grown under conditions that maintain naïve pluripotency exhibit unique metabolic properties, including reduced reliance on catabolism of extracellular glutamine. Despite this, ESCs consume high levels of exogenous glutamine when the metabolite is available. As a result, naïve embryonic stem cells utilize both glucose and glutamine to maintain high levels of intracellular a-ketoglutarate, a metabolite that is critical for the activity of histone and DNA demethylases. High a-ketoglutarate levels promote an open chromatin landscape, thereby inhibiting differentiation and promoting stem cell self-renewal. This work reveals that intracellular a-ketoglutarate levels can contribute to the maintenance of cellular identity and play a mechanistic role in the transcriptional and epigenetic state of stem cells.
 
Coauthors: Bryce W. Carey, PhD2, C. David Allis, PhD2 and Craig B. Thompson, MD1
1 Memorial Sloan Kettering Cancer Center, New York, New York, United States
2 The Rockefeller University, New York, New York, United States

 

A Post-transcriptionally Regulated Metabolic Pathway that enables Liver Metastatic Colonization by Colon Cancer
Sohail Tavazoie, MD, PhD, Associate Professor and Head, Laboratory of Systems Cancer Biology
Jiamin Loo & Alexander Nguyen, Graduate Students
Rockefeller University

For cancer cells to form metastatic colonies, rare cells must achieve optimal gene expression states that enables them to adapt to, and progress within, distal organs. We have found that one mechanism by which cancer cells achieve such pro-metastatic gene expression states is through the modulation of specific miRNAs. By functionally screening 661 miRNAs in parallel during the process of liver colonization, we identified miR-483 and miR-551a as endogenous suppressors of colon cancer liver metastatic colonization. By using these miRNAs as molecular probes, we have identified a metabolic pathway that is utilized by colon cancer cells during liver colonization. MiR-483 and miR-551a convergently target the metabolic enzyme creatine kinase brain-type (CKB). The silencing of these miRNAs enables rare cells to over-express CKB. CKB is known to phosphorylate the metabolite creatine. Loss-of-function, gain-of-function, and epistasis studies reveal CKB to be required for efficient colonization of the liver. Colon cancer cells enter the liver via the portal circulation, which is hypoxemic. We find that CKB is release by colon cancer cells experiencing hypoxia. Previous clinical studies have also detected circulating CKB in the plasma of patients, though the reason for this was not understood. The substrate for CKB, creatine, is produced by the liver. Moreover, CKB-driven metastasis requires extracellular ATP, which is present in the tumor microenvironment. Our observations support a model whereby CKB is release into the extracellular space, where it catalyzes phosphorylation of creatine, yielding phosphocreatine. Phosphocreatine is then imported into the cell, used to generate ATP for fueling metastatic survival. Indeed, phosphocreatine is taken up by colon cancer cells, converted to creatine and ATP, and found to promote colon cancer survival during hypoxia. Analysis of human clinical samples reveals that the expression levels of these miRNAs and CKB supports their experimentally inferred roles in metastatic progression. We furthermore provide proof-of-concept for targeting of this pathway as a means of suppressing colon cancer metastatic progression.
 

Reversible Metabolic Changes in Human Melanoma Cells Enable Distant Metastasis
Elena Piskounova, PhD1

Metastasis is a complex multistep process that requires many cellular adaptations. We developed a mouse model of metastasis, utilizing patient-derived xenografts, which is predictive of metastasis in patients. Functional analysis of melanoma cells from primary subcutaneous tumors, peripheral blood, and metastatic nodules from visceral organs from this model showed that these populations differ in their capacity to form tumors at different sites. Metabolomic profiling of these populations indicated that efficiently metastasizing melanomas undergo reversible metabolic changes as they progress through the metastatic cascade. Specifically, compared to cells from primary subcutaneous tumors, both circulating tumor cells (CTCs) and cells from metastatic nodules had lower Glutathione to Oxidized Glutathione (GSH/GSSG) ratio and higher levels of reactive oxygen species (ROS). Treatment of tumor-bearing mice with antioxidants caused a significant increase in CTC frequency and metastatic burden in distant organs, suggesting that the ability of tumor cells to detoxify ROS is directly linked to their ability to metastasize. Additionally, we observed increased de novo serine synthesis in metastasizing cells, implicating folate/one-carbon metabolism in melanoma metastasis. NADPH production through the folate pathway has been shown to play a key role in maintaining the cellular redox state. Depletion of NADPH-producing enzymes in the one-carbon/folate pathway had a detrimental effect on both CTC frequency and distant metastases, without affecting primary tumor growth. This suggests that successful metastasizers rely on the folate pathway, as a NADPH source, to progress through the metastatic cascade. This work provides insight into the metabolism of metastasis and suggests that enzymes in the folate pathway represent novel therapeutic targets.
 
Coauthors: Michalis Agathocleous, PhD1, Sara E. Mann1, Zeping Hu, PhD1, Zhiyu Zhao, PhD1, A. Marilyn Leitch, MD2, Timothy M. Johnson, MD3, Ralph J. DeBerardinis, MD, PhD1, Sean J. Morrison, PhD1,2
1 Children’s Research Institute at University of Texas Southwestern Medical Center, Dallas, Texas, United States
2 University of Texas Southwestern Medical Center, Dallas, Texas, United States
3 Department of Dermatology, University of Michigan, Ann Arbor, Michigan, United States

 

Identifying Metabolic Dependencies in Pancreatic Cancer
Alec Kimmelman, MD, PhD, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA USA

Pancreatic cancers have an intense resistance to currently available therapeutics which results in a 5-year survival rate of approximately 6%. This resistance points toward altered cell metabolic pathways. In this regard we have previously shown that that oncogenic Kras promotes a rewiring of pancreatic cancer metabolism allowing glucose and glutamine to be utilized in a variety of biosynthetic pathways. Importantly, several of these metabolic pathways are critical for tumor growth and therefore represent potential therapeutic targets. Additional studies from our group have demonstrated pancreatic cancers have elevated basal autophagy which is required for their continued growth. Importantly, inhibition of autophagy pharmacologically or genetically leads to decreased oxidative phosphorylation, a drop in ATP production, and ultimately growth inhibition. These findings have implicated autophagy as a key component of pancreatic cancer metabolism and have motivated the opening of multiple clinical trials assessing the efficacy of hydroxychloroquine as an autophagy inhibitor in pancreatic cancer. Ongoing work form our group seeks to understand the metabolic contributions that autophagy makes in pancreatic tumors. These and other aspects of pancreatic cancer metabolism will be discussed.
 

Cell Cycle Control of Cancer Cell Metabolism
Selina Chen-Kiang, PhD

Cell cycle dysregulation is a hallmark of human cancer. How the cell cycle controls metabolism in cancer cells, however, is not understood. To address this question, we have developed a novel strategy to reprogram cancer cells in prolonged early G1 arrest (pG1) induced by selective inhibition of CDK4/CDK6. pG1, but not normal G1 arrest, results in the expression of genes scheduled in early G1 only and depletion of glycolytic metabolites. This is exacerbated in synchronous S phase entry upon release of the G1 block, due to incomplete restoration of cell cycle-coupled gene expression. We investigated pG1-induced metabolic perturbation in the context of clinical response in a phase I study targeting CDK4/6 with a selective inhibitor palbociclib in combination with the proteasome inhibitor bortezomib in recurrent mantle cell lymphoma (n=16), in which CDK4 is overactivated and cyclin D1 is aberrantly expressed. This therapy achieved a durable response including one complete remission (>900 days) and only one progression at optimal doses. CDK4 inhibition induced pG1 in all patients initially but inactivated PI3K only in clinically responding patients (R). Longitudinal integrative transcriptome and whole exome sequencing of serial biopsies further revealed that <1% of the 1500 genes suppressed (not programmed) in pG1 in Rs were activated in non-responding patients. These genes were critical for metabolism and redox homeostasis.  This study provides the first evidence for cell cycle control of PI3K and metabolism in the context of clinical response, suggesting that metabolic perturbation and redox stress mediates cell cycle reprogramming in cancer cells.
 

Coauthors: Maurizio DiLiberto, PhD, Peter Martin, MD, Jihye Paik, PhD, Costas Lyssiotis, PhD, Qiuying Chen, PhD, Priyanka Vijay, BS, Xiangao Huang, PhD, Olivier Elemento, PhD, Christopher Mason, PhD, Timothy McGraw, PhD, Steven Gross, PhD, John P. Leonard, MD, Lewis Cantley, PhD
 

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