1. McMillan, Daniel R. PhD

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Despite advances in childhood cancer, there are still certain diseases, such as biologically high-risk subsets, cases with advanced disease stage or cases of relapse, where there is just no effective therapy available. These are situations where an experimental therapeutics program can make a difference by providing infrastructure for testing new treatment approaches in "bench-to-bedside" strategies. Developing a successful experimental therapeutics program, even at a prominent pediatric hospital with a long-standing and close association to a major medical center, is a formidable task facing a host of challenges from organization, funding, and staffing to regulatory compliance and controls.

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"Neither Children's Health nor UT Southwestern Medical Center could develop a top-tier program by themselves," said Stephen Skapek, MD, Professor of Pediatrics and Division Director of Hematology and Oncology at UT Southwestern Medical Center and Director of the Pauline Allen Gill Center at Children's Medical Center Dallas. "We are fortunate to be able to draw on the unique and synergistic relationship between the two institutions."


Designing Experimental Therapeutics

The Experimental Therapeutics Program at Children's Health is administered through the Pauline Allen Gill Center for Cancer and Blood Disorders and offers treatment for refractory and relapsed pediatric cancers that can only be found at a few of the nation's top medical centers.


"We see approximately 300 new pediatric cancer patients per year and about one-third of those cases are either refractory to or reoccur after conventional treatment," said Skapek. "Now many patients can receive the latest experimental treatment here and not have to travel to other states-in fact, we have patients from across the state, as well as neighboring states, traveling to us for treatment."


Two other individuals who have played prominent roles in developing the program are Patrick Leavey, MD, Professor of Pediatrics at UT Southwestern Medical Center, Associate Medical Director for Clinical Affairs for the Pauline Allen Gill Center, and the Director of the Musculoskeletal Tumors Program at Children's Medical Center Dallas; and Theodore Laetsch, MD, Assistant Professor of Pediatrics at UT Southwestern Medical Center and leader of the Experimental Therapeutics Program in the Pauline Allen Gill Center at Children's Medical Center Dallas.


"Rather than reinventing the wheel, Leavey and Laetsch travelled to major medical centers across the nation to meet with the research and program leaders of existing top-tier experimental therapeutics programs. Knowledge they gained from those meetings was incorporated into our program's framework to guide our direction, reorganization, and expansion," Skapek noted.


In his administrative role, Leavey reorganized, refined, and expanded the Office of Clinical Research in the Gill Center. "Now we can have a clinical research study set up in as little as 3 months, including scientific review, approval by the Institutional Review Board, and assembling the clinical research coordinators to open and run the study," noted Skapek. As would be expected, their work has been noted and the program has attracted the attention of the larger research community and the pharmaceutical industry.


"We were recently approached by a large pharmaceutical firm to participate in an international study for an immunotherapy treatment of children's leukemia-ultimately, we were one of about 10 sites chosen in the U.S.," said Leavey.


Laetsch coordinated with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern to develop a strong and growing program for early phase clinical trials. "Our program now maintains an average of 18-20 open and accruing phase I and phase II clinical trials, and we have more than tripled the number of patients who enroll in these studies over the last three years," he noted.


Extracranial Solid Tumors

In addition to their roles in the Experimental Therapeutics Program, Laetsch and Leavey both maintain vigorous research programs. Laetsch's interests are centered around the treatment of extracranial solid tumors in children.


"The most common extracranial solid tumors in children are neuroblastoma and sarcoma. Despite recent advances in therapy, patients with metastatic or recurrent disease have a poor overall prognosis. It's clear new advances in therapy are needed," noted Laetsch. He is currently working with a group of investigators at both UT Southwestern and Children's Health on a project consisting of a basic research laboratory component and a translational clinical trial component. Their goal is to utilize magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) in a novel treatment regimen for recurrent solid tumors.


"MR-HIFU is essentially an MRI machine with an ultrasound transducer built into the table. The MRI is used to image a patient and the focused ultrasound delivers energy into the interior of the body to cause localized heating in a noninvasive manner," explained Laetsch.


The resulting effect of the localized heating is vasodilation and increased vascular permeability. The study is utilizing those effects, in conjunction with a modified chemotherapy agent, as a method to increase the dosage and specificity of treatment. One drug they are studying is an investigational medication consisting of doxorubicin encapsulated in a heat-sensitive liposome. Localized heating by MR-HIFU destabilizes the liposome, releasing doxorubicin directly into the area of the tumor.


"In studies with a preclinical tumor model, we have been able to concentrate the effective dose delivery up to 25-fold compared to unheated tumors. In some tumor models this results in a significant tumor growth delay," said Laetsch. Although doxorubicin is a commonly used chemotherapy agent, a particular concern in children is limiting cumulative dose to prevent irreversible myocardial damage. This method has the potential to increase exposure of the tumor to the chemotherapeutic agent while limiting myocardial exposure.


Based on their present results, Laetsch has put together a clinical trial to evaluate the safety of MR-HIFU in combination with liposomal doxorubicin to treat pediatric patients diagnosed with refractory solid tumors. The study should open shortly.


Bone & Soft Tissue Sarcoma

Leavey has a longstanding interest in bone and soft tissue sarcoma and is currently leading a multi-site study to develop a new system to interpret tumor necrosis in osteosarcoma. He noted that "although osteosarcoma is a rare disease, with only 400 newly diagnosed cases per year in the U.S., it is the most common malignant bone sarcoma in children and adolescents, and despite 3 decades of effort, we've essentially been unable to increase the likelihood of a more favorable outcome for our patients."


The current conventional treatment for patients diagnosed with osteosarcoma is 10 weeks of chemotherapy, followed by a surgical procedure to remove the tumor, then followed by an additional 6 months of chemotherapy. In diseases like childhood leukemia, analysis of the treatment response comes quickly and is critical to decision-making for children with this disease, allowing tailoring of therapy for patients based on response. For children with osteosarcoma, pathological response evaluation comes only after 10 weeks of treatment and involves an extensive process in the pathology laboratory, necessitating a manual examination of up to 50 sections of each resected tumor. Leavey hypothesizes that sophisticated computational systems will transform histological interpretation from a binary outcome to an earlier biomarker that will identify patients to be considered for novel treatment.


"Rather simply defined, a biomarker is a measurable characteristic that can be used as an indicator of the normal or diseased state-thus allowing us to quantitate the effect of a therapeutic intervention," noted Leavey.


The initial objective is to develop a computerized image analysis tool that will interpret tumor response at the time of surgery, using histology samples. The study has brought together a multidisciplinary team of investigators, including computer scientists at the University of Texas at Dallas, and pathologists and radiologists at UT Southwestern and Children's Health and the Imaging Center and the 3D Printing Laboratory at Children's Health. While a similar automated pathological evaluation system has been used in certain other types of cancer, their system would be absolutely novel in osteosarcoma.


The ultimate goal of the group is to greatly expand the utility of their innovative image pattern recognition software, essentially dependent on artificial intelligence, to interpret MRI features that predict tumor response.


"This would significantly speed up response analysis and address many of the limitations of our current system," said Leavey. Briefly, the steps toward that goal are to digitize individual pathology slides and to utilize the computer system to build a tumor map, or whole tumor image, for each patient. Using 3D-printed tumor models, Leavey's team will be able to identify co-planar areas for MRI and histological interpretation. Leavey indicates the group is currently 1.5 years into the study and has exciting results they are preparing to share with the research community soon.


DANIEL R. MCMILLAN, PHD, is a Grant and Proposal Writer at Children's Health and Adjunct Assistant Professor at UT Southwestern Medical Center, Dallas.

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