Research & Impact

THE SUNSHINE PROJECT

Sunshine Project is an innovative collaboration with one goal: to bring together the nation’s top doctors and researchers to fast-track less toxic, more targeted treatments and increase the survival rate for children battling cancer.

In 2005, the National Pediatric Cancer Foundation decided to aggressively pursue a measurable change in the way pediatric cancer research was approached and funded by forming the Sunshine Project.

Through the establishment of the Sunshine Project, the National Pediatric Cancer Foundation has developed a business model unlike any other in the field of pediatric cancer research. Capitalizing on the strengths of researchers from a variety of scientific fields, we have streamlined the process of protocol development in the hopes of delivering more personalized medicine to children with cancer.

Through the Sunshine Project, the National Pediatric Cancer Foundation has launched five Phase 1 clinical trials in just eight years. This is an incredibly short time in the medical world. New combinations have been, and continue to be, tested in these trials. These new combinations hold great promise for children who have not experienced positive results under the standard protocol treatment.

HOW IS THE SUNSHINE PROJECT UNIQUE?

The collaborative effort that is engaged through the Sunshine Project is a fast-growing consortium of the nation’s top pediatric researchers.

Investigators are performing three vital phases of research simultaneously. Basic science, translational research, and clinical trials are the major research components that not only allow doctors to identify new agents in fighting cancer but also help researchers to understand the cancer cells’ response to the drug. To identify new treatment options through clinical trials, researchers focus on developing treatments that target only cancer-causing molecules in the body, unlike more traditional treatments that often prove toxic to healthy cells. Because the new gene-targeted therapies are less toxic than traditional treatment, it is also more effective because it targets the source of the cancer and does not compromise the rest of the body by eliminating the immune system, which many times leads to death.

The Sunshine Project is being executed at a rapid rate, relying on the cooperative efforts of a team of principal investigators from leading institutions. Through this novel approach, the National Pediatric Cancer Foundation is literally changing the way research is done.


CLINICAL TRIALS OVERSIGHT COMMITTEE

The Clinical Trials Oversight Committee (CTOC) is a group of pediatric oncologists who specialize in phase 1 clinical trials. This group of physicians reviews and evaluate the conduct of each trial the National Pediatric Cancer Foundation conducts. Every quarter, the CTOC meets to ensure all clinical research conducted or coordinated by NPCF is scientifically well designed, responsibly managed, appropriately reported, and protects the rights and welfare of human participants.

The CTOC provides an independent review of the interim results of each trial and offers objective guidance regarding unforeseen events that may occur during the course of a study. The CTOC will help to evaluate and ensure events that may have an impact on patient safety are appropriately addressed and managed on an on-going basis.

At the quarterly meetings, discussions will include adverse events, accrual, and protocol deviations. Adverse event and deviation collection begin when a patient is first placed on trial. All events are classified using the NCI Common Toxicity Criteria and are summarized and presented to all members at each safety meeting.

Oversight Committee Institutions


TRANSLATIONAL RESEARCH

The Sunshine Lab has performed drug screening against 5 different diseases that impact children and adolescents – Alveolar Soft Part Sarcoma (ASPS), Ewing Sarcoma, Malignant Peripheral Nerve Sheath Tumors (MPNST), Osteosarcoma, and Rhabdomyosarcoma.

SCIENTIFIC OVERVIEW

Drugs are screened across multiple established cell line models for each disease. We have tested 140 unique, individual agents so far, at multiple concentrations. Selected agents are either FDA-approved, clinically promising, or experimentally interesting. The drug concentrations we test are determined based on several factors, most important being published pharmacokinetics. We make the best possible effort to ensure drugs are tested at clinically achievable and physiologically relevant conditions. From these individual agents, we have screened over 250 combinations of agents at an average of 25 different concentrations for each combination. In other words, we have obtained data for over 6,000 different two-drug regimens altogether across these 5 diseases. To do this, we have teamed up with the translational research core at Moffitt Cancer Center in Tampa, FL. Pooling our resources together, we employ 3 liquid handling robots, 2 plate readers, multiple sterile hoods, and all the basic tools necessary to generate high quality, high confidence data. In addition to the important task of finding promising new treatment regimens for these diseases, we use cutting-edge technology to investigate the molecular biological mechanisms underlying these cancers. Combining our library of screening data with our biochemical studies allows us to better understand each individual disease so that we can focus in on the chemotherapeutics that are most likely to provide good results in the clinic. Since 2013, we have published 4 original research articles and currently have 2 more in the submission process. We have shared our data with the scientific community at the American Association of Cancer Researchers (AACR) annual conference every year starting in 2014. We have also presented our data at conferences and symposia hosted by the Children’s Tumor Foundation (CTF), Connective Tissue Oncology Society (CTOS), John’s Hopkins All Children’s Hospital (JHACH), Cancer Prevention & Research Institute of Texas (CPRIT), and others.

THE GOAL

The overall goal of these studies performed on cell lines and models, is to identify promising drug combinations for the treatment of pediatric sarcomas. Most importantly, the molecular targets for our trials will have been identified prior to the trial initiation. Thus, the translation of the laboratory findings to the clinical setting will not be primarily empiric, but rather based on a molecular understanding of drug/target and drug/drug interactions.


CLINICAL TRIALS AND INITIATIVES

A Phase I Trial of Dose Escalation of Metformin in Combination with Vincristine, Irinotecan, and Temozolomide in Children with Relapsed or Refractory Solid Tumors

Principal Investigator: Damon Reed, MD (Moffitt Cancer Center)

Study Synopsis: An FDA approved clinical trial focused on relapsed or refractory solid tumors in children. Solid tumors account for 60% of all childhood malignancies and unlike other childhood cancers, minimal improvement in survival has been seen in the past 20 years. These disappointing results have prompted NPCF to find new agents in the fight against this disease.

Metformin is an oral anti-diabetes medication. Recent data from research experiments and analyses of previous data suggest that Metformin has anti-cancer activity. The drugs vincristine, irinotecan and temozolomide, also known as VIT, are a combination of chemotherapies that have different ways of working and different side effects. This combination has been shown to be safe and well tolerated in children with solid tumors. This trial is evaluating the tolerability and safety of increasing doses of Metformin in combination with vincristine, irinotecan, and temozolomide in children with solid tumors.

Phase II Study of nab-Paclitaxel in Combination with Gemcitabine for Treatment of Recurrent/Refractory Sarcoma in Teenagers and Young Adults

Principal Investigator: Javier Oesterheld, MD (Carolinas Medical Center/Levine Cancer Institute)

Study Synopsis: Patients who have recurrent or progressive disease following frontline treatment for osteosarcoma or Ewing sarcoma have a dismal prognosis, with less than one-fifth of patients achieving a long-term cure. Although many adolescents and young adults with localized bone or soft tissue sarcoma can become long-term survivors, more effective therapies are needed for patients who present with metastatic disease or whose tumors recur after completing therapy.

 It is thought this combination will be more tolerable and effective than other relapsed regimen used to treat this population.  This trial will look at this combination of nab-paclitaxel and gemcitabine in its ability to prevent the formation or growth of tumors in teenagers and young adults with relapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and other soft tissue sarcomas.  Markers for response to therapy are cutting edge in this trial and include blood tests to determine if the cancer is responding, computer-assisted imaging reviews to determine better ways to follow disease, and biomarkers on the tumor specimens to see if a response can be predicted.

ACTION: Adoptive Cellular Therapy following Dose-Intensified Temozolomide in Newly-diagnosed Pediatric High-grade Gliomas

Principal Investigator: Duane Mitchell, MD, Ph.D. (University of Florida)

A Phase I Trial of Dose Escalation of Metformin in Combination with Vincristine, Irinotecan, and Temozolomide in Children with Relapsed or Refractory Solid Tumors

Study Synopsis: ACTIoN is an innovative immunotherapy trial for the treatment of high-grade gliomas (HGG) in children. Pediatric brain tumors like HGG are now the leading cause of cancer-related deaths in children in the United States due to the advances in the treatment of more common hematologic malignancies. Current treatments such as surgical removal of the tumor, radiation, and chemotherapy can cure many patients with other types of brain tumors; however, the prognosis for children with high-grade gliomas (HGGs) remains poor.

It is believed that the body’s immune system protects the by attacking and killing tumor cells. T-lymphocytes (T-cells) are part of the immune system and can attack when they recognize special proteins on the surface of tumors. But in most patients with high-grade gliomas (HGGs), T-cells are not stimulated enough to kill the tumor. In this trial, the patient’s tumor will be used to make a vaccine which will hopefully stimulate the T-cells to kill the tumor cells, while leaving the normal cells alone.

Phase 1 Trial of the LSD1 inhibitor sp-2577 in patients with relapsed or refractory Ewing sarcoma     

Principal Investigator: Damon Reed, MD, Moffitt Cancer Center

Study Synopsis: This trial is a targeted treatment for individuals diagnosed with refractory or recurrent Ewing sarcoma. Ewing sarcoma is an aggressive, small round blue cell tumor typically presenting as a primary bone tumor in children and young adults.

This trial will be testing SP-2577, a reversible inhibitor of LSD1, an enzyme that targets EWS/FLI1 activity; the critical pathophysiologic mechanism of Ewing sarcoma, through disruption of the function of associated proteins represents an intriguing strategy for clinical intervention. This concept has been featured in Nature News, an international science publication.

Pediatric Total Cancer Care (pedsTCC)

Principal Investigator: Damon Reed, MD (Moffitt Cancer Center)

Study Synopsis: This tissue and blood banking trial was launched in 2013 with the focus to further personalize medicine for children with cancer. PedsTCC has always aimed to be a foundation from which clinicians could answer specific questions related to their patient’s cancer through the use of molecular testing. These test results can have a significant impact on the patient’s choice of therapy. Indeed rigorous studies of rare cancer and a rare patient have launched from this foundation across institutions bringing national experts to an individual’s care.

Preclinical Study of Anti-PD-1 Antibody in Combination with 5-Azacytidine in Mouse Models of Osteosarcoma

Principal Investigators: Richard Gorlick, MD (MD Anderson Cancer Center), Michael Roth, MD (Children’s Hospital at Montefiore), David Loeb, MD, Ph.D. (Johns Hopkins University), Nicolas Llosa, MD (Johns Hopkins University), Brian Ladle, MD, PhD (Johns Hopkins University), Ian Davis, MD, Ph.D. (University of North Carolina at Chapel Hill), Patrick Thompson, MD (University of North Carolina at Chapel Hill)

Study Synopsis: This study explores the ways in which certain drugs, epigenetic modifiers, change the immune system and cancer. We plan to leverage the results of this unique, 3 institution collaboration towards the development of future Sunshine Project clinical trials such as an emerging concept for assessing the therapeutic utility of checkpoint inhibitors in combination with 5-azacitidine in patients with osteosarcoma.

Osteosarcoma outcomes have not significantly improved over the past three decades. This preclinical proposal has clear translational benefits. By defining the biology and efficacy of combined therapy with an anti-PD-1 antibody and 5-azacytidine, researchers hope to establish the basis for developing this approach into a potential Sunshine Project clinical trial for children with relapsed or refractory osteosarcoma.

Role of myeloid-derived suppressor cells (MDSC) in the development of immune tolerance after allogeneic hematopoietic cell transplantation (alloHCT).

Principal Investigator: Benjamin Oshrine, MD (Johns Hopkins All Children’s Hospital)

Study Synopsis: This trial is for children and young adults undergoing a bone marrow transplant (BMT) for treatment of leukemia or lymphoma. This research is being done to better understand the process of developing immune tolerance after blood and marrow transplantation (BMT). After BMT, the immune system of the donor gradually learns to recognize the recipient as “self” to avoid problems like graft-versus-host disease, a common complication of BMT. This is called immune tolerance. Researchers hope to determine if one specific type of immune cell, called “myeloid-derived suppressor cells” (MDSCs), are involved in this process and to determine when this cell remerges after transplant.Blood will be collected from study participants undergoing BMT to compare recipients of matched related and unrelated transplants to those receiving haploidentical bone marrow transplants (from half-matched relatives).