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Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team

Overview

Finding the cancer therapies of tomorrow requires visionary thinking and innovative research today. The Van Andel Research Institute–Stand Up To Cancer (VARI–SU2C) Epigenetics Dream Team fosters collaboration between several of the world’s most respected research and clinical organizations in an effort to translate scientific discoveries into new standards of patient care. The goal is simple—get new and more effective cancer therapies to patients faster.

What are epigenetics? Why study it?

If the genetic code is a musical score, then epigenetics represents the various ways in which it may or may not be played. Although the actual notes on the sheet music do not change, the choice of tempo, instrument, volume and even the omission of parts of the piece alters what the listener hears. In much the same way, epigenetic modifications do not change the DNA sequence—which is virtually identical in all cells in a person’s body—rather, they regulate how the DNA is expressed. Epigenetics control how the DNA is used, switching particular genes “on” or “off” to determine cell type and function.
In the majority of human cancers, there are errors in the genome and the epigenome and these errors can contribute to cancer development, growth and treatment resistance. Identifying and understanding how these errors arise and how to correct them holds great promise for developing new, more effective therapies.

About the team

The VARI–SU2C Epigenetics Dream Team was established in 2014 and builds on the foundations laid by the first iteration of the SU2C Epigenetics Dream Team, which was founded in 2009. Today’s team is based at Van Andel Research Institute in Grand Rapids, Michigan, and is led by the Institute’s Chief Scientific Officer Peter Jones, Ph.D., D.Sc., and Stephen Baylin, M.D., VARI professor and co-head of Cancer Biology at Johns Hopkins University’s Sidney Kimmel Comprehensive Cancer Center. The team includes leading scientists and clinicians with vast experience in translating basic science and promising therapies from the lab to the clinic.

The team is honored to be affiliated with Stand Up To Cancer, a program of the Entertainment Industry Foundation. Launched in 2008, SU2C draws on the resources of the entire entertainment industry to encourage the public to support research conducted by teams of scientists, as well as by individual investigators. To date, more than 1,100 researchers from more than 130 institutions in seven countries have collaborated across SU2C’s 19 Dream Teams, six Translational Research Teams and 36 Innovative Research Grants.

Rigorous and objective scientific oversight and review is provided by SU2C’s scientific partner, the American Association for Cancer Research (AACR), the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer.

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VARI-SU2C Epigenetics Dream Team members

Peter Jones, Ph.D, D.Sc. (Dream Team co-leader)
Chief Scientific Officer
Van Andel Research Institute

Stephen Baylin, M.D. (Dream Team co-leader)
Co-head of Cancer Biology; Virginia and D.K. Ludwig Professor for Cancer Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Professor, Van Andel Research Institute

Anthony El-Khoueiry, M.D.
Associate Professor of Clinical Medicine, Clinical Instructor—Division of Medical Oncology
University of Southern California

Kirsten Grønbæk, M.D., D.M.Sc.
Professor, Chief Physician
University of Copenhagen/Rigshospitalet

Jean-Pierre Issa, M.D.
Director—Fels Institute for Cancer Research and Molecular Biology
Temple University/Fox Chase Cancer Center

Patricia Kropf, M.D.
Deputy Director, Bone Marrow Transplant Program
Temple University/Fox Chase Cancer Center

Feyruz Rassool, M.D.
Associate Professor
University of Maryland School of Medicine

Charles Rudin, M.D., Ph.D.
Chief—Thoracic Oncology Service
Memorial Sloan Kettering Cancer Center

Ongoing VARI–SU2C Epigenetics Dream Team trials

Below is information about ongoing VARI-SU2C Epigenetics Dream Team trials. Please note, although Van Andel Research Institute is involved in clinical trials, the Institute does not treat patients nor are trials conducted onsite. Information about additional clinical trials beyond those conducted by VARI-SU2C Epigenetic Dream Team members can be found at clinicaltrials.su2c.org.

Metastatic colorectal cancer

This trial further tests a combination therapy for metastatic colorectal cancer that includes a drug called guadecitabine (also known as SGI-110), which may correct errors in methylation, a common epigenetic process that determines whether a gene is switched on or off. Genes that are inappropriately switched off do not produce proteins needed for normal function and can contribute to diseases such as cancer. The purpose of this trial is to test whether guadecitabine can reverse resistance to a standard therapy, irinotecan, which many patients with advanced colon cancer frequently develop.
Nationally, an estimated 134,490 people will be diagnosed with colorectal cancer in 2016, according to the National Cancer Institute, and over 49,000 will die. The high mortality rate is due in part to colorectal cancer’s tendency to aggressively spread, or metastasize, to other organs. Epigenetic therapies have the potential to directly treat cancer or to sensitize tumors to traditional treatments.

Trial name:Phase I study of SGI-110 with irinotecan followed by randomized phase II study of SGI-110 with irinotecan versus regorafenib or TAS-102 in previously treated metastatic colorectal cancer
ClinicalTrials.gov number:
 NCT01896856
Principal investigator:
 Nilofer Azad, M.D., Sidney Kimmel Comprehensive Cancer Center
Co-principal investigator:
 Nita Ahuja, M.D., Sidney Kimmel Comprehensive Cancer Center
Trial locations
: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
University of Southern California, Los Angeles, California
Memorial Sloan Kettering Cancer Center, New York, New York
VU University Medical Center, Amsterdam, The Netherlands
Industry partner: Astex Pharmaceuticals, Inc.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) (EVITA trial)

New findings published recently in the Proceedings of the National Academy of Sciences showed in lab studies that supplementing an epigenetic cancer drug called decitabine with vitamin C enhanced the drug’s ability to impede cancer cell growth and trigger cellular self-destruction in cancer cell lines. A pilot clinical trial based on this work is ongoing in adult patients with MDS or AML at Rigshospitalet in Copenhagen, Denmark. It combines a similar drug called azacitidine —the standard of care therapy—with vitamin C. Many cancer patients are deficient in vitamin C; the proposed approach seeks to correct this deficiency rather than overload patients with the vitamin.

Maintaining proper nutrition is an important part of cancer therapy. Patients are urged to consult their doctors before making any change to their nutrition or vitamin regimen. Use of vitamin C may preclude patients from participating in a clinical trial. At this point, this effect has only been shown in cell lines, and the efficacy in patients can only be confirmed through a rigorous and controlled trial.

An estimated 13,000 people in the U.S. are diagnosed with MDS annually and about 20,000 are diagnosed with AML. Currently, only about half of patients with MDS and AML respond to the epigenetic therapy alone.

Trial name: Epigenetics, vitamin C and abnormal hematopoiesis—pilot study (EVITA-pilot)
ClinicalTrials.gov number: NCT02877277
Principal investigator: Kirsten Grønbaek, M.D., DMSc., Rigshospitalet/Univeristy of Copenhagen
Trial location: Rigshospitalet, Copenhagen, Denmark

Acute myeloid leukemia (relapsed and refractory)

The trial pairs an investigational PARP inhibitor, talazoparib, with the DNA methyltransferase (DNMT) inhibitor decitabine, which is already approved for the treatment of myelodysplastic syndrome (MDS), a disease that often precedes AML. Preclinical studies show that combining the drugs may maximize their ability to kill cancer cells.

AML begins as abnormal blood cells in the bone marrow and spreads throughout the circulatory system and beyond, if not diagnosed and treated quickly. Almost 20,000 people in the U.S. are diagnosed with AML every year.

Trial name
Decitabine and talazoparib in untreated AML and R/R AML
ClinicalTrials.gov identifier: NCT02878785
Number of patients: 171
Clinical sites: University of Maryland Greenebaum Comprehensive Cancer Center, Fox Chase Cancer Center and University of Southern California


For more information, please visit ClinicalTrials.gov.

Publications of interest

The names of Dream Team members are bolded.

Publications

Muvarak NE, Chowdhury K, Xia L, Robert C, Choi EY, Cai Y, Bellani M, Z Y, Singh ZN, Duong VH, Rutherford T, Nagaria P, Bentzen SM, Seidman MM, Baer MR, Lapdius RG, Baylin SB, Rassool FV. In press. Enhancing the cytotoxic effects of PARP inhibitors with DNA demethylating agents–a potential therapy for cancer. Can Cell.

Liu M, Ohtani H, Zhou W, Ørskov AD, Charlet J, Zhang YW, Shen H, Baylin SB, Liang G*, Grønbæk K*, Jones PA*. In press. Vitamin C increases viral mimicry induced by 5-aza2’-deoxycytidine. Proc Natl Acad Sci U S A.
*Co-senior authors

Lok BH, Gardner EE, Schneeberger VE, Ni A, Desmeules P, Rekhtman N, de Stanchina E, Teicher BA, Riaz N, Powell SN, Poirier JT, Rudin CM. In press. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clin Cancer Res.

Yamazaki J, Taby R, Jelinek J, Raynal NJ, Cesaroni M, Peirce SA, Kornblau SM, Bueso-Ramos CE, Ravandi F, Kantarjian HM, Issa JP. 2016. Hypomethylation of TET2 target genes identifies a curable subset of acute myeloid leukemia. J Natl Cancer Inst 108(2).

Issa JP, Roboz G, Rizzieri D, Jabbour E, Stock W, O’Connell C, Yee K, Tibes R, Griffiths EA, Walsh K, Daver N, Chung W, Naim S, Taverna P, Oganesian A, Hao Y, Lowder JN, Azab M, Kantarijian H. 2015. Safety and tolerability of guadecitabine (SGI-1110) in patients with myelodysplastic syndrome and acute myeloid leukemia: A multicenter, randomized dose-escalation phase 1 study. Lancet Oncol 16(9):1099–1110. 

Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, Han H, Liang G, Jones PA, Pugh TJ, O’Brien C, De Carvalho DD. 2015. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162(5):961–973.

Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, Makarav V, Buhu S, Slamon DJ, Wolchok DJ, Pardoll DM, Beckmann WM, Zahnow CA, Mergoub T, Chan TA, Baylin SB, Strick R. 2015. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162(5):974–986.

Yamazaki J, Jelinek J, Lu Y, Cesaroni M, Madzo J, Neumann F, He R, Taby R, Vasanthakumar A, Macrae T, Ostler KR, Kantaijian HM, Liang S, Estecio MR, Godley LA, Issa JP. 2015. TET2 mutations affect non-CpG island DNA methylation at enhancers and transcription factor-binding sites in chronic myelomonocytic leukemia. Cancer Res 75(14):2833–2843.

VARI-SU2C Epigenetics Dream Team News