Sarah Howard

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The Research Grant

The progress made in the treatment of pediatric brain tumors has been woefully inadequate. Brain tumors are now the most common cause of cancer related death in children and are the most common solid tumor of childhood. The clinical research community is dependent upon an understanding of the biology of these tumors in order to construct rational clinical research trials using new biological inhibitors of key pathways. Biologic discovery is the current bottleneck in the creation of new innovative therapeutic strategies.

Tumor suppressor genes normally function to control cellular proliferation. When tumor suppressor genes are inactivated, normal growth controls are removed and tumors can result. HIC1 is a tumor suppressor gene important in childhood brain tumors including glioma, ependymoma and medulloblastoma. It resides in a region of the genetic code that is often damaged in childhood brain tumors leading to the inactivation of HIC1. Because HIC1 functions to turn off other genes, its inactivation allows for the expression of genes that should normally be silent. Those expressed genes result in tumor formation and therefore represent potential therapeutic targets. This proposal seeks to silence HIC1 in the normal cells that become transformed into tumor cells, thereby recapitulating the process under experimental conditions. This will allow us to interrogate the transformed cells in comparison to the parental cells to determine which pathways are critical for tumor formation. This knowledge will facilitate the identification of therapeutic targets for new drugs.

Dr. Brian Rood’s Perspective

The illuminating experience of observing Dr. Rita Meek, a pediatric oncologist, kneeling to speak face to face with a young child while that child’s mother observed the interaction with an affectionate smile gave me insight into the humility, humanism, and high stakes that characterize pediatric oncology. I had cultivated an interest in the human condition during my studies of literature in college and the nature of suffering in medical school; I also knew that communication was one of my strengths. This dynamic interaction showed me a field which integrated the key elements of dedication, communication and humanism.

Now, fifteen years later, I can not conceive of a career more challenging or more rewarding. The challenges are numerous and polymorphic: navigating complex healthcare delivery systems, obtaining research funding, employing novel therapies, discussing mortality with parents and children, and developing clinical programs. As overwhelming as the challenges can seem, they pale in comparison to the reward of being trusted by a family to play an important role in their lives through what will be the most trying experiences they will ever face. The privilege inherent in that position can not be overstated or underappreciated.

When I began fellowship training, I believed that I was interested in oncology mainly for the humanistic aspects of the field. I did not have a particular interest in research but planned to avail myself of the opportunity to explore it. During those two years, I became fascinated with the creativity that is integral to research. Through the research, I became quite knowledgeable about the tumor types that I was studying. That knowledge in turn increased my confidence in seeing patients and I began to experience the satisfaction of being able to help in some way those families facing extreme challenges. I had now found a sub-specialty that fit my particular skills and that provided me with a sense of purpose. In order to begin to move down that path, I did an additional year as a research fellow and clinical associate working in neuro-oncology. I became certain that the path of physician scientist in neuro-oncology held for me the things I most desired: the opportunity to be creative, deep interpersonal relationships with families, the intellectual stimulation of an ever evolving field and a role in trying to improve the future chances of children stricken with these devastating diseases.

My initial experience in the lab revolved around a project investigating the deletion and methylation status of a tumor suppressor gene on 17p called HIC1 in medulloblastoma. This work led to my first publication in the area of cancer research. HIC1 is a fascinating and frustrating gene. Its protein product represses the transcription of other genes and has been found to be inactivated by deletion and epigenetic silencing in multiple tumor types including childhood medulloblastoma and ependymoma in the brain. However, the identity of the genes that HIC1 represses was not known. Turning my attention to this problem led to another fulfilling reward, the discovery of a generous collaborator and mentor in France, Dominique Leprince. Dr. Leprince was one of only a few investigators working on HIC1 at the time and had identified the elements controlling HIC1’s activation as well as the mechanisms it used to silence other genes. He shared reagents with me and we began a collaboration with the ambitious goal of identifying the genes that HIC1 controls. This work has led us around many corners confronting issues such as tissue specificity, species differences, and the bi-directionality of repression/activation. Along the way, our collaboration led to the identification (and publication) of the HIC1 DNA binding site, a necessary piece of knowledge for identifying target genes. Recently, we published a paper identifying a receptor involved in cancer cell migration as a target of HIC1 repression. We have also published an invited review article on HIC1 and broadened the collaboration to include groups in New York, Switzerland and the Czech Republic. It is beginning to appear that HIC1 is a master control gene involved in development, aging and tumor formation. It has been gratifying to have been on the ground floor of the HIC1 field and to see its evolution as it has engendered the interest and involvement of more scientists.

The realization that HIC1’s effects are tissue specific has led me to realize another aspect of this career path, the ability to creatively solve problems by crossing traditional boundaries. Following where HIC1 was leading me, I realized that I needed to expand my horizons beyond traditional cancer research and into neuroscience. In order to create and interpret a model of the tumorigenic effects of HIC1 in a child’s developing brain, it would be necessary to silence HIC1 in neural cells that are in the process of development and interrogate the phenotype and function of those cells. The tools for doing this are to be found in the field of developmental neuroscience. In order to pursue this area, I have obtained an NIH career development award with mentors from both cancer research and neuroscience. I am now using neuroscience techniques used to map the fate of developing neural cells and to introduce a genetic construct that silences HIC1 in neural stem cells in embryonic mice.

Despite our best efforts to cure pediatric tumors with chemotherapy and radiation and despite our efforts to identify new therapeutic avenues through research, many children still die. I have found in myself the ability to remain open to families in pain to help them through their tragic journeys. What I can not accept, and what deprives me of peace, is when children suffer. As a physician, it is my duty to heal, not simply to cure. I also believe that healing comes in as many forms as suffering and must be flexible, multidisciplinary, patient focused, and inclusive of the many facets of a patient’s existence. These beliefs motivated me to lead a team devoted to the development of palliative care services at CNMC called the Pediatric Advanced NeeDs and Assessment team (PANDA). We quickly realized that the need for palliative care is not unique to the Oncology division and we have now expanded our services throughout the institution. We have an education program for residents and fellows, perform inservices in various care areas, and provide consultative services for children with life limiting illnesses. We received grant funding from the Lance Armstrong Foundation and support from the Stewart Trust to develop this program. We have also worked with the Ethics Committee to change the hospital’s Do Not Resuscitate policy to one of Allow Natural Death, reframing this difficult discussion with families in a way that removes the assumption of maximal medical intervention without expected benefit. The PANDA service continues to grow and we are striving to change the culture of practice at CNMC to one that recognizes how the patient experiences their health in order to provide truly comprehensive care aimed at healing.

One of the most dramatic measures of the PANDA program’s success is the formation of the District of Columbia Pediatric Palliative Care Collaboration (DCPPCC). For many years, the District’s children facing end of life could not die at home receiving the benefits of hospice care because no such service existed. We joined with HSC Pediatric Center and Community Hospices to form the DCPPCC, a non-profit corporation to develop quality standards, best practice models, research platforms, and oversight capabilities for the provision of hospice and palliative care services to the children of the District. I sit on the board of the DCPPCC and serve as its Secretary and Medical Director of Research. The dream of providing hospice care to the District’s children was realized in February of 2008 when we opened the Gemstones program through Community Hospices, a pediatric hospice and palliative care program providing multidisciplinary care to children with life limiting illnesses. We have also written and submitted a waiver application in order to change the Medicaid fee structure to recognize the unique needs of this population. We have forged corporate partnerships with Deloitte and Patten Boggs and held three national conferences. I have had the pleasure to speak at two of them on the topics of “Ethical End-of-Life Choices” and “Quality of Life”. I am particularly proud of this venture because we built it from the ground up and it has made a real, positive change in the care received by an extremely vulnerable population of children.

Caring for children who are afflicted with cancer is the most satisfying career I can imagine. As my roles have evolved, I have found a balance between the immediate needs of my patients and the long term objectives of improving treatments through research, between treating tumors and healing patients and families by contending with their suffering. I have experienced many close relationships with families in dire straights. Each has presented different challenges but all have been rewarding. It is from them that I draw the desire to improve clinical programs, discover new therapeutic avenues, teach the next generation and grow in my own skills. Although the work can be taxing, I feel a sense of purpose and perspective that I would not trade for an easier path.