Oxidative Stress in Cancer and Exploitation of Negative Regulators as Therapeutics

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Oxidative Stress in Cancer and Exploitation of Negative Regulators as Therapeutics

Thursday, February 10, 2011

The New York Academy of Sciences

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Reactive oxygen and nitrogen species (RONS), including free radicals like superoxide and nonradicals such as hydrogen peroxide and peroxynitrite, occur naturally in the course of normal oxygen consumption and metabolism. However, since RONS can dramatically alter the structure and function of proteins, lipids, and nucleic acids, they can be highly toxic to cells and have been implicated in the pathogenesis of some diseases, including cancer and inflammatory disorders. Interestingly, since reduction/oxidation (redox) reactions that generate RONS are fundamental to life, and despite the fact that they can be injurious, nature has nevertheless exploited redox reactions that produce RONS to its advantage. Notably, RONS are a necessary component of normal inflammatory processes since they are effective in killing infectious microbes and fungi. In addition, many receptor-ligand interactions, including those involving certain cytokines and growth factors, result in immediate generation of RONS for the purpose of propagating normal proinflammatory signaling. But because excess amounts of RONS are highly toxic, nature has also evolved endogenous negative regulators that suppress their generation. Imbalance in the generation and suppression of RONS, which can be caused by overproduction or inhibition of endogenous negative regulators, results in “oxidative stress,” and this condition is linked to many disease states. While it is generally accepted that excessive oxidative stress induces apoptosis, it is less well known that moderate oxidative stress, by promoting proliferation, metastasis, and avoidance of apoptosis and the immune system, imparts a survival advantage to tumor cells. A better understanding of underlying mechanisms that regulate the generation and metabolism of RONS provides a rationale for developing novel therapeutics for treating cancer. For example, selective pharmacologic suppression of RONS in cancer patients has been shown to provide a meaningful clinical benefit. The role of RONS in disease and the development of innovative drugs that modulate oxidative stress, particularly in the treatment of cancer, is the topic of this symposium.

Networking reception to follow.

Sponsor


This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.

Agenda

*Presentation times are subject to change.


1:00 PM

Welcome and Introduction

1:10 PM

Mechanisms of Action of Synthetic Triterpenoids in Suppression of Oxidative Stress
Michael B. Sporn, MD, Dartmouth Medical School

1:50 PM

Biology and Regulation of Nitric Oxide in Human Melanoma
Elizabeth A. Grimm, PhD, MD Anderson Cancer Center

2:30 PM

Reactive Oxygen Species and Tumor Cell Resistance to Cytotoxic T Cells
Dmitry Gabrilovich, MD, PhD, H. Lee Moffitt Cancer Center

3:10 PM

Coffee Break

3:40 PM

Biological, Translational, and Clinical Rationale for the Development of Anti-Cancer Therapeutics that Suppress Oxidative Stress
Colin Meyer, MD, Reata Pharmaceuticals, Inc.

4:20 PM

The Role of Oxidative Stress in the Pathogenesis of Regimen-Related Toxicities of Cancer Therapy
Stephen T. Sonis, DMD, DMSc, Harvard/Farber Cancer Center

5:00 PM

Networking Reception

Speakers

Organizers

Colin Meyer, MD

Reata Pharmaceuticals, Inc.

George Zavoico, PhD

MLV

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Dmitry Gabrilovich, MD, PhD

H. Lee Moffitt Cancer Center

Dmitry Gabrilovich, MD, PhD is a Senior Member at the Moffitt Cancer Center in the Immunology Department and is a Professor of Oncologic Sciences and Molecular Medicine at the University of South Florida. He and his co-workers are investigating abnormalities in immune responses in cancer. He was one of the first investigators who described tumor associated defects in dendritic cell function in cancer. He is one of the pioneers in discovering critical role played by myeloid-derived suppressor cells in inability of host immune system to control tumor growth. His current research is focused on understanding the mechanisms of tumor-associated immunosuppression and on the development of new and effective cancer vaccines. Dr. Gabrilovich has published more than 130 peer-reviewed publications with many of them in top level journals.

Elizabeth A. Grimm, PhD

MD Anderson Cancer Center

Dr. Grimm is a Professor at the University of Texas MD Anderson Cancer Center Department of Experimental Therapeutics, as well as Deputy Head of Division of Cancer Medicine. Her research is divided into two major areas: (a) fundamental cancer biology related to cytokine expression and inflammation in apoptosis resistance pathways which are based on her findings of endogenous constitutive nitric oxide in production in the tumor cells patients with the worst prognosis; and (b) translational studies developing new therapies and validating prognostic markers in human melanoma. Dr. Grimm is also a Professor of two University of Texas educational programs; one in the Immunobiology of Cancer, and the second in Cancer Biology Program at the Graduate School of Biomedical Sciences. She successfully organized and was awarded the first NIH T32 Training Grant supporting the Cancer Biology graduate program and administered the program as the PI of the training grant for a decade. She has personally mentored and supervised numerous fellows, graduate and postdoctoral students, including those from the MD/PhD program which two are currently completing their PhD research in her laboratory.

Her pioneering research in the 1980’s at the NCI on human cytokines, particularly IL-2, led directly to its development as approved agent for melanoma therapy. More recently, in an attempt to reveal mechanisms of IL-2 resistance, her research has led to a focus on “carcinogenic inflammation” which is associated with melanoma expression of various deleterious inflammatory markers, particularly inducible nitric oxide synthase (iNOS) which is proposed as a marker of poor prognosis, as well as a target for therapy.

Dr. Grimm has received continuous peer-reviewed NIH funding for over 20 years since arriving at MDACC, and most recently successfully organized and was awarded the first NCI SPORE dedicated completely to Melanoma, in 2004. Dr. Grimm has authored and co-authored over 160 publications in peer-reviewed journals, and over 60 book chapters, and served on NIH and ACS peer review and executive councils, as well as lead AACR and ASCO annual meeting programs in immunology and melanoma. Dr. Grimm is in demand as a speaker and organizer at national and international conferences and symposia.

Colin Meyer, MD

Reata Pharmaceuticals, Inc.

Dr. Meyer is the Vice President, Product Development of Reata Pharmaceuticals and joined the company as its second employee. Dr. Meyer's primary role is to develop and implement strategies to move product candidates expeditiously through all stages of development. His duties include overseeing all preclinical development, determining relevant primary and surrogate endpoints for clinical studies, and developing clinical strategies for the drug candidates. Dr. Meyer received a BS in chemistry with specialization in biochemistry and a BA in biology from the University of Virginia. He received an MD from the University of Texas Southwestern Medical School and an MBA from Southern Methodist University Cox School of Business.

Stephen T. Sonis, DMD, DMSc

Harvard/Farber Cancer Center

After receiving his DMD from Tufts University, Dr. Sonis entered a combined doctorate and clinical specialty training program at Harvard University. Following completion of his degree and residency, he was awarded a Knox Fellowship to study tumor immunology at Oxford University. He returned to the United States to accept joint positions at the Peter Bent Brigham Hospital, Sidney Farber Cancer Center, and the Harvard School of Dental Medicine.

Dr. Sonis’ research converged on studies to define the biology and clinical significance of cancer regimen-related mucosal toxicities. The results of his studies on the molecular and cellular pathogenesis of mucositis have established the basis of a mechanistic paradigm for epithelial injury, and have provided treatment targets for biological and pharmaceutical development. Recognizing that genetics play a role in patient risk for mucositis and other toxicities, Dr. Sonis and his collaborators have identified specific canonical pathways that are critical in toxicity development and have used these to form the basis for models of gene-based risk prediction. With the application of network theory to cancer-related toxicities, Dr. Sonis and his colleagues have built on earlier work to define specific toxicity constellations in patients receiving chemotherapy. Dr. Sonis has broad experience in clinical trial design, implementation and endpoint quality management. Many of his former students and residents now hold academic and clinical leadership positions.

Dr. Sonis has published extensively on the clinical, biological, and health economic aspects of cancer and complications associated with its treatment. He is the author of over 200 original publications, reviews and chapters, 7 books, and 5 patents. He has lectured extensively on the clinical and biological aspects of cancer regimen-related toxicities and cancer diagnostics. Dr. Sonis serves on a number of editorial boards, and is a founding member of the International Society of Oral Oncology and the International Academy of Oral Onocology.

Michael B. Sporn, MD

Dartmouth Medical School

Michael B. Sporn, MD is Professor of Pharmacology and Medicine at Dartmouth Medical School. Over his career he has been involved extensively in studies of nucleic acids (both RNA and DNA), retinoids (vitamin A and its synthetic analogs), and peptide growth factors (especially transforming growth factor beta, TGF-beta). TGF-beta was first isolated, purified and characterized in his laboratory at the National Institutes of Health in the 1980’s. In 1995 he moved his laboratory to Dartmouth, and since then he has been involved in the development of new synthetic triterpenoids for the prevention and treatment of many diseases including cancer. The ability of synthetic triterpenoids to suppress inflammatory and oxidative stress forms a mechanistic basis for much of this work. He has published more than 400 papers in peer-reviewed journals.

Supporters

For sponsorship opportunities, please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.

This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.

Grant Support

This activity is supported by an educational grant from ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company. For further information concerning ImClone Systems grant funding visit www.imclonegrantoffice.com.

This event is funded in part by the Life Technoogies™ Foundation.

Promotional Partner

American Association for Cancer Research

Fondation IPSEN

Abstracts

Mechanisms of Action of Synthetic Triterpenoids in Suppression of Oxidative Stress

Michael B. Sporn, MD, Dartmouth Medical School

We will cover the pharmacological basis for the use of synthetic oleanane triterpenoids in suppression and treatment of carcinogenesis. We will first discuss the chemical synthesis of new oleanane triterpenoids and then briefly review their overall efficacy in several cancer models. Particular emphasis in this talk will be placed on the ability of triterpenoids to prevent cancers in experimental models of breast, lung, and pancreatic cancer, and the mechanistic basis for these findings.

Biology and Regulation of Nitric Oxide in Human Melanoma

Elizabeth A. Grimm, PhD, MD Anderson Cancer Center

In our previous studies we found that the presence of inducible nitric oxide synthase (NOS) protein levels in both primary and metastatic melanoma was prognostic for poor survivial; our recent work continues to determine the genetic and pharmacologic regulation of its constitutive expression. The results confirmed that iNOS protein is readily detectable in melanoma cell cytoplasm in the majority of patients, and the quantity, as detected by immunohistochemistry (IHC), provides prognostic information by identifying patients with poor survival in both univariate and multivariate analysis (p<0.001), independently of AJCC staging and associated prognostic criteria. Melanomas are recognized to be heterogeneous based on etiology and somatic mutational status and have aberrant expression of inflammatory genes and proteins. We now expand the testing of iNOS protein expression as a clinically useful prognostic marker and propose that iNOS represents a “node” of an identifiable melanoma inflammatory and oxidative stress network.  We further hypothesize that a “signature of poor prognosis” for melanoma can be generated by directly testing tumors for expression of iNOS-related inflammatory markers.

Testing for association of iNOS protein expression and levels with both genetic alterations (mutations of BRAF and NRAS) and mitogen-activated protein kinase (MAPK) pathway activation was also performed in a large series of primary cutaneous tumor biopsies. We report that active MAPK can drive iNOS expression and that inhibition of MAPK and/or BRAF inhibits iNOS protein expression. iNOS protein in melanoma was also found to be sensitive to down regulation by pharmacologic agents, possibly for therapeutic advantage. Pharmacologic inhibition of iNOS or inhibition of its product, nitric oxide (NO), restores chemosensitivity in iNOS-positive melanoma cell lines. Building on these results, data from three new areas will now be presented:

1) identify iNOS-related inflammatory marker genes expressed in melanoma, as part of a proposed signature, 2) determine which candidate marker proteins can be identified in melanoma tumors by standard immunohistochemistry and whether their presence adds value to the iNOS survival prediction model, and 3) test the inflammatory stress pathway as a target for melanoma patient therapy in clinical trials using anti-inflammatory drugs that inhibit either expression of iNOS and/or the resultant NO or other inflammatory mediators. In summary, the biology and regulation of NO-driven inflammation in melanoma is considered as a critical aspect for controlling this devastating cancer.

Reactive Oxygen Species and Tumor Cell Resistance to Cytotoxic T Cells

Dmitry Gabrilovich, MD, PhD, H. Lee Moffitt Cancer Center

We present a concept that failure of cytotoxic T lymphocytes (CTL) generated ex vivo to eliminate tumor after adoptive transfer into tumor-bearing hosts can be independent on tumor-associated immune suppression and is mediated by reactive oxygen species. Major feature of tumor infiltrating myeloid cells is a production of large amount of peroxynitrite (PNT). In mice, myeloid-derived suppressor cells (MDSC) were a primary source of PNT. Pre-treatment of tumor cells with PNT or with MDSC inhibited binding of processed peptides to tumor cell associated MHC. As a result tumor cells became resistant to antigen-specific CTLs. This effect was abrogated in MDSC with a defect in the production of reactive oxygen species or after treatment with the PNT inhibitor. As a model of tumor associated inflammation, we used Lewis lung carcinoma (LLC) cells overexpressing IL-1ß and ovalbumin (OVA). Adoptive transfer of antigen-specific CTLs after total body irradiation significantly reduced growth of LLC-OVA tumors. In contrast, the therapeutic effect was completely blocked in LLC-OVA-IL-1ß tumor-bearing mice. Therapeutic failure was not caused by more profound suppression of T cells in IL-1ß expressing tumors. Pharmacological inhibition of PNT dramatically enhanced the effect of adoptive transfer in LLC-OVA-IL-1ß tumor-bearing mice.

Biological, Translational, and Clinical Rationale for the Development of Anti-Cancer Therapeutics that Suppress Oxidative Stress

Colin Meyer, MD, Reata Pharmaceuticals, Inc.

Mounting evidence suggests that oxidants are not simply by-products of metabolism.  Rather, these highly reactive and transient molecules are produced endogenously and used to regulate inflammatory reactions in a rapid, feed-forward manner.  These same inflammatory pathways, which are activated in innate and adaptive immunity, are also exploited in the setting of carcinogenesis, as well as tumor growth, invasion, and metastasis.

One particular class of endogenous mediators, the cyclopentenone prostaglandins, has evolved to regulate and suppresses oxidant-mediated signaling.  The primary cellular target of the cyclopentenone prostaglandins is the Keap1-Nrf2 pathway, which regulates the production of antioxidant enzymes, enzymes involved in glutathione synthesis and homeostasis, and enzymes involved in detoxification and transport of xenobiotics.  In addition to generally suppressing oxidative stress, this pathway has been shown to directly interact with and suppress the IKK-NF-kB axis.  Similarly, NF-kB has also been shown to negatively suppress the Keap1-Nrf2 pathway.  Evidence from the literature demonstrates that suppression of Keap1-Nrf2 and activation of NF-kB is a common molecular theme among cancers.

Bardoxolone methyl and related members of the AIM class of compounds are the most potent known inducers of the Keap1-Nrf2 pathway.  They modulate signaling pathways involved in tumor growth, survival, and metastasis, and suppression of the anti-tumor immune response.  These molecules have shown anti-cancer and tissue protective activity not only in preclinical models of cancer but in patients.    

This talk will highlight recent biological advances and data supporting the use of potent suppressors of oxidative stress in the treatment of cancer.

The Role of Oxidative Stress in the Pathogenesis of Regimen-Related Toxicities of Cancer Therapy

Stephen T. Sonis, DMD, DMSc, Harvard/Farber Cancer Center

Regimen-related toxicities result in much of the morbidity that is associated with both drug and radiation therapy used to treat cancer. The historical paradigm suggested that much tissue-targeting toxicity, including injury to the gastrointestinal tract, was simply the consequence of the non-specific impact of cytotoxic agents on rapidly dividing normal cells. However, this concept has been largely overturned in the past decade and replaced by one which favors a biologically complex pathoetiology.

Oral mucositis is one of the most common, distressing, and resource-intense toxicities of cancer treatment. Its biology provides an excellent model to illustrate the molecular sequence of chemotherapy- and radiation-induced tissue injury and to examine a pivotal role for oxidative stress in the process. In addition, the potential for reactive oxygen species to serve as pharmacological targets for the prevention and treatment of mucosal injury is illustrative of a therapeutic approach in which normal cells injury is attenuated in the absence of tumor cell protection.

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