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eBriefing

Therapeutic Advances in Cancer Metabolism and Signaling

Therapeutic Advances in Cancer Metabolism and Signaling
Reported by
Kari Fischer

Posted July 31, 2020

Presented By

Cancer Discussion Group

The New York Academy of Sciences

The observation that cancer cells often have fundamentally different metabolic activities than their normal counterparts has led to resurgent interest in the field of cancer metabolism, and the designation of altered metabolism as a hallmark of cancer. Evidence suggests that cancer cells can leverage metabolic pathways to enhance survival, fuel proliferation, and even promote migration and distant metastatic colonization. Moreover, metabolites can act as signals or inhibitors that directly regulate chromatin-modifying enzymes, thereby influencing cell fate decisions that can be critical for cancer progression. These findings collectively suggest that targeting metabolic pathways provides new therapeutic strategies for the treatment of various cancer types. However, several of the metabolic alterations evident in cancer cells are also present in highly proliferative healthy cells, complicating attempts to safely and specifically target cancer cells. Therefore, it is critical to understand metabolic abnormalities in cancer, how oncogenic drivers trigger such changes, and whether metabolic differences represent viable targets for therapy.

The annual Cancer Metabolism and Signaling conference, held virtually on April 17, 2020, convened experts to discuss the defining features of cancer cell metabolism, and metabolic regulation in tumor progression and metastasis.

In this eBriefing, You’ll Learn:

  • Advances in the understanding of iron metabolism and cancer progression
  • The latest findings on the role of autophagy in cancer metabolism
  • How metabolism affects T Cell responses in cancer
  • Potential metabolic targets in cancer metastasis

Keynote Speaker

Joshua D. Rabinowitz, PhD

Princeton University

Speakers

Sarah-Maria Fendt, PhD
Sarah-Maria Fendt, PhD

VIB-KU Leuven Center for Cancer Biology

David J. Pagliarini, PhD
David J. Pagliarini, PhD

Washington University School of Medicine in St. Louis

Rushika M. Perera, PhD
Rushika M. Perera, PhD

University of California, San Francisco

Richard L. Possemato, PhD
Richard L. Possemato, PhD

NYU School of Medicine

Eileen White, PhD
Eileen White, PhD

Rutgers Cancer Institute of New Jersey

Adrienne Boire, MD, PhD
Adrienne Boire, MD, PhD

Memorial Sloan Kettering Cancer Center

John Blenis, PhD
John Blenis, PhD

Weill Cornell Medicine

Russell Jones, PhD
Russell Jones, PhD

Van Andel Institute

Fendt/Pagliarini

Speakers

Metastasis Metabolism - Cancer Cells Are What They Eat

Sarah-Maria Fendt, PhD
VIB-KU Leuven Center for Cancer Biology

Sarah-Maria Fendt is a Principal Investigator at the VIB Center for Cancer Biology and Assistant Professor of Oncology at KU Leuven, Belgium. Sarah has a Master degree of Science in Biochemistry from TU Munich and a PhD in Molecular Systems Biology from the ETH Zurich. Sarah worked has postdoc at the MIT, before joining VIB as an independent VIB group leader in 2013. Sarah’s lab is specifically interested in elucidating general regulatory principles in metabolism, and understanding cancer metabolism during metastasis formation as well as during altered nutrient availability. To perform novel research in her fields of interest her group exploits their expertise in metabolomics and fluxomics. The research of Sarah’s lab is currently funded by multiple (inter)national grants and industry, which include an ERC consolidator grant. Sarah received several awards such as the Conquer-Cancer-Now and the Grants4Targets award.

Defining Mitochondrial Protein Function through Systems Biochemistry

David J. Pagliarini, PhD
Washington University School of Medicine in St. Louis

Dave Pagliarini is a Professor and BJC Investigator at Washington University School of Medicine. Prior to moving to St. Louis, Dave was the Lead Investigator and Arthur C. Nielsen Jr. Chair of Metabolism at the Morgridge Institute for Research and an Associate Professor of Biochemistry at the University of Wisconsin-Madison. After graduating with honors in from the University of Notre Dame, Dave received a Ph.D. in biochemistry under the direction of Jack Dixon at UC San Diego, and performed his postdoctoral research with Vamsi Mootha at Harvard Medical School/The Broad Institute. At WashU, Dave leads an interdisciplinary team of scientists focusing on a range of leading-edge challenges in mitochondrial biochemistry and metabolism. In particular, Dave’s lab blends large-scale systems approaches with mechanistic biochemistry to define the molecular underpinnings of mitochondria dysfunction in human disease. Dave has received a number of honors for his work, including a Searle Scholar Award, the Presidential Early Career Award for Scientists and Engineers (PECASE), the Young Investigator award from the Protein Society, and the Earl and Thressa Stadtman Young Scholar Award from the ASBMB. He lives in St. Louis with his wife, Carrie, and their two sons.

Metastasis Metabolism - Cancer Cells Are What They Eat/Defining Mitochondrial Protein Function through Systems Biochemistry


Sarah-Maria Fendt/David J. Pagliarini (VIB-KU Leuven Center for Cancer Biology/Morgridge Institute for Research; University of Wisconsin-Madison)

Further Reading

Fendt

Elia I, Rossi M, Stegen S, et al.

Nature. 2019;568(7750):117-121

Altea-Manzano P, Broekaert D, Duarte JAG, et al

Pagliarini

Perera/Possemato

Speakers

New Players and Unique Features of Cancer Lysosomes

Rushika M. Perera, PhD
University of California, San Francisco

Rushika grew up in Australia and received her PhD degree from the University of Melbourne and the Ludwig Institute for Cancer Research studying EGFR signaling in Glioblastoma. She conducted studies at Yale University in the laboratories of Derek Toomre and Pietro De Camilli in the department of Cell Biology. Here she used live cell microscopy techniques to determine the topography and dynamics of endocytic vesicular trafficking. She later completed postdoctoral training at Massachusetts General Hospital Cancer Center/Harvard Medical School in the laboratory of Nabeel Bardeesy where she uncovered mechanisms for increased lysosome biogenesis and function in pancreatic cancer.

Targeting Iron Metabolism

Richard L. Possemato, PhD
NYU School of Medicine

Dr. Richard Possemato has been an Assistant Professor in the Department of Pathology at NYU School of Medicine since 2015. His graduate work focused on studying cellular transformation models under the advisement of Dr. William Hahn at the Dana Farber Cancer Institute, and his post-doctoral work focused on identifying metabolic liabilities of cancer in the laboratory of Dr. David Sabatini at the Whitehead Institute. The Possemato lab seeks to understand the metabolic pathways that are altered in cancer, the processes that these altered pathways support, and the environmental, genetic, and epigenetic contexts in which these pathways are important. To that end, they focus on several key areas including (1) ironsulfur cluster biosynthesis and cellular iron metabolism, (2) liver models of tissue regeneration and transformation, and (3) metabolic liabilities imposed by nutrient limitation.  Awards from the Pew Charitable Trusts, Margaret  Stewart  Foundation, Susan G. Komen for the  Cure, Gabrielle’s Angel  Foundation, and  Howard  Hughes  Medical Institute have recognized Dr.  Possemato.

New Players and Unique Features of Cancer Lysosomes/Targeting Iron Metabolism


Rushika M. Perera/Richard L. Possemato (University of California, San Francisco/NYU School of Medicine)

Further Reading

Perera

Yamamoto K, Venida A, Yano J, et al.

Nature. 2020;581(7806):100-105

Venida A, Perera RM

Cell Metab. 2019;29(2):236-238

Perera RM, Di Malta C, Ballabio A

Annu Rev Cancer Biol. 2019;3:203-222

Possemato

Alvarez SW, Sviderskiy VO, Terzi EM, et al

Nature. 2017;551(7682):639-643

Alvarez SW, Possemato R.

Oncotarget. 2018;9(13):10830-10831

White/Boire

Speakers

Role of Autophagy in Cancer Metabolism

Eileen White, PhD
Rutgers Cancer Institute of New Jersey

Eileen White, Ph.D., is the Deputy Director, Chief Scientific Officer, and Associate Director for Basic Research at the Rutgers Cancer Institute of New Jersey, an NCI-designated Comprehensive Cancer Center. Current research focuses on the role of autophagy and metabolism in cancer. Dr. White has served on the Board of Scientific Counselors of the National Cancer Institute and other review panels for the National Institutes of Health.  She is the recipient of numerous awards including a MERIT award from the National Cancer Institute, the Red Smith award from the Damon Runyon Cancer Research Foundation, a Howard Hughes Medical Institute Investigatorship, an Achievement Award from the International Cell Death Society, a Career Award for the European Cell Death Organization, and is an elected Fellow of the American Society of Microbiology (ASM) and the American Association for the Advancement of Science (AAAS).  Dr. White has also served as a member of the Board of Directors of the American Association for Cancer Research (AACR), the Scientific Review Boards for the Starr Cancer Consortium, the Damon Runyon Cancer Research Foundation, and the Cancer Prevention Research Institute of Texas (CPRIT). She is on the External Advisory Boards of the Stanford, Yale, MD Anderson, Hollings, Case, and MGH Comprehensive Cancer Centers.

The Signaling and Metabolic Landscape Associated with Metastatic Progression

Adrienne Boire, MD, PhD
Memorial Sloan Kettering Cancer Center

Adrienne Boire, M.D., Ph.D. is a physician-scientist at Memorial Sloan Kettering Cancer Center in New York. After undergraduate work in Biology at Macalester College, she completed her Ph.D. in Biochemistry at Tufts University in 2004 under the mentorship of Athan Kuliopulos, M.D., Ph.D. She then earned an M.D. at the University of Chicago Pritzker School of Medicine in 2008, followed by residency in Neurology at Columbia Presbyterian Hospital and fellowship in Neuro-Oncology at Memorial Sloan Kettering Cancer Center. After completing a post-doctoral fellowship under the guidance of Joan Massagué, Ph.D., she joined the Human Oncogenesis and Pathology Program at MSKCC as an assistant member in 2017. As a neuro-oncologist, she cares for patients with metastasis to the central nervous system (CNS) and conducts clinical trials targeting these tumors. As a scientist, she runs a laboratory-based research program focused on metastasis to the CNS, both leptomeningeal and parenchymal metastases. The laboratory employs multiple complementary approaches to identify and target cancer cell adaptations to the challenging microenvironmental constraints posed by the CNS.

Role of Autophagy in Cancer Metabolism/The Signaling and Metabolic Landscape Associated with Metastatic Progression


Eileen White/Adrienne Boire

Further Reading

White

Yang Y, Karsli-Uzunbas G, Poillet-Perez L, et al.

Genes Dev. 2020;34(9-10):688-700

Poillet-Perez L, White E

Genes Dev. 2019;33(11-12):610-619

Mehnert JM, Panda A, Zhong H, et al

J Clin Invest. 2016;126(6):2334-2340.

Boire

Boire A, Zou Y, Shieh J, et al.

Cell. 2017;168(6):1101-1113.e13

Glitza IC, Smalley KSM, Brastianos PK, et al

Pigment Cell Melanoma Res. 2020;33(4):527-541

Boire A, Brastianos PK, Garzia L, Valiente M

Nat Rev Cancer. 2020;20(1):4-11

Blenis/Jones

Speakers

The Signaling and Metabolic Landscape Associated with Metastatic Progression

John Blenis, PhD
Weill Cornell Medicine

Dr. Blenis has made pioneering contributions to our understanding of the PI3K-mTOR-S6K and Ras-ERK/MAPK pathways, set the conceptual framework for how they are organized and regulated, and identified and characterized downstream regulatory mechanisms and therapeutic targets now targeted in cancer clinical trials. In the early days, he purified S6K and defined its activation by mitogens and oncogenes, discovered its activation was blocked by rapamycin and established it as the first component of what we now call the mTORC1 pathway. He defined how mitogenic signals regulate the tumor suppressor TSC2 and the RHEB GTPases as part of the canonical pathway for mTORC1 activation. More recently, he demonstrated how mTORC1 effector kinases, SRPK2 and GSK3, regulate mRNA biogenesis and cell metabolism. Dr. Blenis also defined Ras-dependent regulation of ERK and RSK. He discovered that Raf, ERK, and RSK form a Ras-modulated kinase cascade, that ERK and RSK translocate into the nucleus, and that ERK and RSK signal strength, duration and location are central to cell fate decisions. These fundamental discoveries were critical for understanding how ERK and RSK regulate cell survival, migration and proliferation. Dr. Blenis continues to identify biomarkers, therapeutic targets and drug resistance mechanisms that will enable future treatment strategies.

Metabolic Regulation of T Cell Responses

Russell Jones, PhD
Van Andel Institute

Dr. Russell (Rusty) Jones is a Professor in the Center for Cancer and Cell Biology and head of the Metabolic and Nutritional Programming research group at the Van Andel Institute in Grand Rapids, Michigan. His research focuses on investigating the genetic and biochemical pathways that control metabolic reprogramming in cancer and the immune system. Dr. Jones received his Ph.D. in Medical Biophysics in 2003 from the University of Toronto and completed post-doctoral training with Dr. Craig Thompson at the University of Pennsylvania. One goal of Dr. Jones’ research is to investigate how cellular metabolism can be used to target the metabolic vulnerabilities of cancer cells, and how we can enhance immune responses to cancer through metabolic interventions.  Dr. Jones was previously an Associate Professor in the Department of Physiology and Goodman Cancer Research Centre at McGill University, where he was a William Dawson Scholar. Dr. Jones was recipient of the Dorval Young Investigator Prize from the Canadian Cancer Society in 2014. The Canadian Institutes of Health research (CIHR), The Canadian Cancer Society, The Terry Fox Foundation, The Cancer Research Society, and The Canadian Foundation for Innovation have supported his work.

The Signaling and Metabolic Landscape Associated with Metastatic Progression/Metabolic Regulation of T Cell Responses


John Blenis/Russell Jones (Weill Cornell Medicine/Van Andel Institute)
Keynote/Q&A

Speakers

Keynote: A Tale of Two Cofactors: Folate and NADPH

Joshua D. Rabinowitz, PhD
Princeton University

Joshua Rabinowitz is a Professor of Chemistry & Integrative Genomics at Princeton University. He brings a quantitative, chemical perspective to the study of diet and metabolism. His research focuses on two broad questions: What is the quantitative flow (flux) through different metabolic pathways? How is this flux controlled? To address these questions, his lab develops innovative technologies that blend mass spectrometry, isotope tracers, and computational data integration. These technologies have been broadly applied to address major biomedical problems, including diabetes, infectious disease, and cancer. In the field of oncology, Dr. Rabinowitz contributed to the discovery of the cancer-causing metabolite, 2-hydroxyglutarate. More recently, his work found that lactate, classically considered a waste product, is actual a major circulating fuel.  Prior to Princeton University, Dr. Rabinowitz led R & D efforts at Alexza Pharmaceuticals where he invented the first thermal aerosol drug delivery product, the Adasuve inhaler, approved by the FDA for rapid treatment of agitation. Dr. Rabinowitz received both his Ph.D. in Biophysics followed by his M.D. from Stanford University.

Keynote: A Tale of Two Cofactors: Folate and NADPH


Joshua D. Rabinowitz (Princeton University)

Further Reading

Rabinowitz

Fan J, Ye J, Kamphorst JJ, Shlomi T, et al

Nature. 2014;510(7504):298-302

Zhang Z, Chen L, Liu L, et al

J Am Chem Soc. 2017;139(41):14368-14371

Yang L, Garcia Canaveras JC, et al

Cell Metab. 2020;31(4):809-821