Metastatic pheochromocytoma is a rare cancer of the adrenal gland that typically occurs in adults 20 to 40 years of age, but it can strike children as young as in their early teens. There is no cure for the disease – yet. The Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute proposes to change that by using cutting-edge genetic information to create treatments tailored to patients. The Lerner Research Institute invites you to become a key partner in research by supporting this groundbreaking project. Together donors and researchers compose a formidable team uniquely qualified to provide real solutions. To understand the tremendous opportunity at hand, we first provide some background:

Cleveland Clinic, one of the largest and most respected health care centers in the world, is a multi-specialty academic-medical institution that seamlessly integrates clinical treatment with research and education. As a world-renowned leader in both basic and clinical research, Cleveland Clinic enjoys a long history of successful research innovation. A strong alignment between research and patient care has remained a constant and powerful guide for our institution, yielding an extensive legacy of medical innovations. As the foundation for all of our medical advances, our careful, painstaking laboratory work provides the means for improved patient care.

Today, all of Cleveland Clinic’s basic laboratory, translational and clinical research is conducted at the Lerner Research Institute (LRI). This research epicenter comprises more than 190 Principal Investigators in 11 specialized departments consisting of: Biomedical Engineering, Cancer Biology, Cell Biology, Genomic Medicine, Immunology, Molecular Cardiology, Molecular Genetics, Neurosciences, Pathobiology, Quantitative Health Sciences, and Stem Cell Biology, and Regenerative Medicine. The focus of the Lerner Research Institute is to find cures for some of today’s most debilitating diseases. Currently we are leading major efforts in the following disease areas: cardiovascular disease, cancer, allergic/immunologic, infectious diseases, metabolic diseases, musculoskeletal diseases, neurologic diseases, and diseases of the eye.

With an international reputation for conducting science that is on the cutting edge, the LRI attracts scientists, fellows, and post-doctorate fellows from around the world. These research leaders and future leaders come to our campus to study, collaborate with our scientists, and take part in our pioneering research projects. With a firm commitment to translating laboratory discoveries into groundbreaking improvements in clinical practice, the LRI and its team of scientists are transforming the practice of medicine – for today and tomorrow.

The emerging concept of personalized medicine has been embraced at the highest levels of Cleveland Clinic. Currently, the standard of medical care is for patients to see their physicians upon expression of a symptom or symptoms. It is only at that time, and perhaps after a battery of testing, that a diagnosis can be made and treatment can be initiated. With this model, however, the disease has been given an opportunity to progress to a point where temporary or permanent discomfort is experienced by the patient. Equally important, this current model of medicine does not emphasize individualized treatment plans, which often reduce a patient’s recovery time. Founded in 2005, the Genomic Medicine Institute was created to shift this current paradigm of reactive medicine to one that is proactive in nature.

The Genomic Medicine Institute is led by its founder, Charis Eng, MD, PhD, FACP, a world-renowned human cancer genomicist who has orchestrated tremendous advances in genomic medicine. Most notably, Dr. Eng discovered the tumor-suppressing gene PTEN that predisposes the development of breast and thyroid cancers. As a trainee in the University of Cambridge lab of leading cancer scientist Professor Bruce Ponder, Dr. Eng discovered the first pheochromocytoma gene (RET) and helped identify a second. In the past eight years, she has led an international consortium that has discovered and characterized the other three (SDHB, C, D) pheochromocytoma-predisposition genes. Furthermore, her consortium has enabled gene-based diagnosis and prediction that has led to the development of screening and treatment via genetics and genomics-based personalized healthcare.

The Genomic Medicine Institute incorporates both research facilities and a clinical practice, allowing research breakthroughs to seamlessly translate into improved patient care. Laboratory insights into the underlying causes of metastatic pheochromocytoma will create new diagnostic tools, treatments and therapies, improving the care and health of our patients.

Recent advances in biomedical research have revolutionized cancer treatment, and the near future holds exceptional promise. We now have more effective treatments, expanded capabilities for cancer screening and prevention, and new opportunities for research. Despite these advances, many forms of incurable cancers still exist. However, by exploring the frontiers of genomic medicine, we will gain the knowledge to improve interventions and identify cures.

Pheochromocytoma is one type of cancer that stands to benefit from further research at this time. Pheochromocytoma is a tumor of the adrenal medulla, which produces adrenaline or the “fight or flight” hormone. Pheochromocytoma and the related paraganglioma are unusual cancers, many of which occur in childhood and young adulthood. Many pheochromocytoma are technically not malignant and cannot spread outside the organ of origin, in this case, the adrenal gland. However, pheochromocytoma can super-produce adrenaline, which can result in severe high blood pressure, stroke, and even death. The treatment of pheochromocytoma is complex due to the misunderstanding that non-malignant cancers are not life threatening. In addition, doctors are unable to determine malignancy via imaging (CAT scan, X-ray, etc) or microscopic examination. Therefore, they have resorted to an operational definition of what is considered malignant: if a pheochromocytoma is found outside the organ of origin, then it is malignant because it has metastasized.

Unfortunately, standard treatment methods for this group of cancers cannot be relied upon. In the 1960’s, chemotherapy was a breakthrough in treating cancers. For the first time, cancers regressed, but they always returned. Still, for nearly five decades, the principle method of treating cancers was to create agents that take advantage of the rapid growth of cells. This also meant that normal body cells that grow faster than the rest – blood cells and gut cells especially – were also affected by these treatments (accounting for the side effects of chemotherapy). A chemotherapeutic drug trial could claim success when there was a certain percentage response rate, but it could never be predicted which percentage.

Phaeochromocytomas and PGL’s are called neuroendocrine tumors. They are usually benign, but when they are malignant, they tend to grow more slowly than most cancers. This slower movement means that typical chemotherapies, and even radiochemicals, are not as effective. SDHB or D mutations are associated more with malignant pheochromocytoma, which may mean it is amenable to anti-angiogenic targeted therapies. This theory is based upon current level of knowledge about these genes. Thus, an out-of-the-box strategy may involve researching whether utilizing the SDH enzyme for enzyme replacement could cure metastatic SDHB/D-associated pheochromocytoma and PGL.

Genomic medicine holds the key to understanding metastatic pheochromocytoma and the development of more effective treatment strategies. While it was once believed that only 10% of pheochromocytoma were due to inherited genetic causes, Dr. Eng and her colleagues have found that at least one-third are due to inherited genetic and genomic causes. Over the last decade, they have also discovered that there are at least five different genes which, when altered or mutated, cause inherited pheochromocytoma. Because of the genes involved, these pheochromocytoma behave differently than non-inherited (sporadic) pheochromocytoma. If they act differently, then understanding the genetic and genomic bases of the various inherited and sporadic pheochromocytoma will allow us to tailor personalized therapies. Most importantly, only two of the genes associated with inherited pheochromocytoma signal a high likelihood of malignancy: SDHB and SDHD genes, with SDHB gene mutations having a much higher likelihood of malignant pheochromocytoma than SDHD. Discovering why SDHB is different from SDHD, and why they are different from the other three genes, is vital to understanding malignant potential and metastases. This knowledge will eventually lead to personalized therapies with improved cure rates.

Knowing which genes are mutated in an individual is key. This knowledge enables an accurate gene-based diagnosis, allowing for the prediction of which unaffected family member may inherit the same mutated gene. If we know that a family has the malignancy-associated SDHB mutation, heightened lifelong screening can be implemented to catch the disease early when it is curable. Understanding gene alterations will also assist physicians in selecting the appropriate therapy. If a correct therapy does not exist, as it does not in this case, then we must tailor new treatment strategies beyond traditional drug development, whether through tailored molecular-targeted drugs or other non-drug compounds/strategies. Without fully understanding the underlying genetics of malignant-prone versus benign-prone pheochromocytoma, we cannot be successful in efforts for prevention or a cure.

To this end, Dr. Eng and her colleagues have created a two-pronged approach. First, clinical characteristics will be comprehensively delineated, which will be stored in a database, and linked to mutations and each of the five genes. Second, the genomic differences will be delineated between pheochromocytoma with a propensity to be malignant and to metastasize, and those that are truly benign. This process will allow for the creation of individualized, molecular-targeted treatments and prevention strategies for metastatic pheochromocytoma.

Major advances in genetics, genomics, technology, and bioinformatics as well as drug development make this an opportune time for this ambitious undertaking. The human genome was mapped in 2003, and clinical context has accumulated. Due to the 13 years of work conducted by Dr. Eng and her international consortium, clinical context in the pheochromocytoma field has been realized at a quicker pace, thus allowing for the application of clinical meaning to a genetic finding (as above: e.g., SDHB = high likelihood of malignancy).

The era of molecular tailored therapies began with the discovery of Gleevac, which targets a specific gene mutation in leukemia and rare tumors such as gastrointestinal stromal tumors. Targeted tailored therapies seek out the altered gene product like a “smart bomb.” When we understand all the gene alterations in malignant pheochromocytoma, we can also develop such a treatment for metastatic pheochromocytoma.

What does the story of Gleevac have to do with the story of Pheochromocytoma? Gleevac is a drug tailored to seek out a very specific gene alteration in the rare and incurable leukemia Chronic Myeloid Leukemia (CML). It worked – complete remissions and cures became reality. Drug resistance also developed in some patients. By further studying genetics, scientists found out the genetic reason for resistance and developed a second generation of drugs to overcome this acquired resistance. Gleevac was then used for many other cancers beyond CML. More importantly, Gleevac was used as a model of tailored therapies for many other common and uncommon cancers, such as lung cancer.

Gleevac does not work in pheochromocytoma. But it gives great hope! Cure pheochromocytoma by studying its genetics and beyond and we cure many other types of cancers.

Based on previous research and current drug development timelines, we propose the following timeline for developing tailored therapies for patients suffering from malignant pheochromocytoma:

At Cleveland Clinic, philanthropy is the crucial link between our current excellence of care and our ability to deliver future medical breakthroughs and innovative treatments. Such innovative projects are difficult to fund, particularly in light of the National Institutes of Health’s recent decision to cut research funding for 2009. Therefore, we seek the support of individuals, such as you, who share our vision in improving the lives of patients who are and will battle this form of cancer thought to be “uncurable.” We respectfully invite you to partner with us through a gift to reach a total goal of $5 million to enable Dr. Eng and her colleagues to advance this project to the clinical trial stage over a four-year period.

Ways in which you can partner in this endeavor are as follows:

Consider making a tax-efficient, multiyear pledge to provide ongoing support for the work of Dr. Eng and her colleagues.

Consider a cash gift or a “Gift of Assets”. Both giving methods provide you with charitable deductions and also offer additional tax savings. Gifts of assets may include: Stock and securities (including bonds, mutual funds); Real estate; Life insurance; Retirement plans (including IRAs); Personal property (including artwork, collectibles and jewelry); and Business interests.

Please know that however you chose to support these efforts, your commitment has the extraordinary potential to improve the lives of countless individuals for many years to come. Every gift is important and valued. For more details, or to discuss how your gift can make a difference to research, please contact the office of philanthropy at 216.444.1821 or (800) 223.2273 x41821. To learn more about the LRI please visit our website at http://www.lerner.ccf.org/ and to learn more about the Genomic Medicine Institute please go to http://www.lerner.ccf.org/gmi/.