Brain tumors are the most common solid tumor in children and represent the leading cause of death from childhood cancer. Diffuse intrinsic pontine gliomas (DIPG) are a highly aggressive pediatric brain tumor of the brain stem, with a five-year survival rate of less than 1% and median survival of only 9 months. While significant improvement in survival has been achieved in treating other forms of brain cancer, the outcome for children with DIPG has remained poor, and has not changed in over three decades.
The major challenge in the treatment of DIPG is its extremely invasive nature and delicate anatomical location in the brain stem, which precludes surgical removal. Previous research has shown that transplanted neural stem cells (NSC) possess remarkable tropic migratory capacity toward adult brain tumors, but the use of NSCs in clinics is severely limited by the ethical and technical challenges to obtain these cells in human. Furthermore, current approaches rely on viral-based vectors for delivery of therapeutic genes, which face safety concerns for broad clinical applications. While gene therapy targeting tumor apoptosis has been shown to be effective in eradicating adult brain tumors, pediatric brain tumors including DIPG, easily gain drug resistance to apoptosis inducing-based gene therapy alone.
Through working at the interface of biology, material science, bioengineering and medicine, this Alliance for Cancer Gene Therapy funded research will develop a novel treatment regimen to enhance targeting and eradication of disseminated DIPG tumor by directing addressing the current critical bottlenecks in the field of cancer gene therapy.
To overcome the critical barrier of cell availability by employing adipose-derived stem cells (ADSCs), an abundant and easily accessible autologous stem cells source as drug delivery vehicle for targeting DIPG cells in vivo.
Unlike the conventional, viral vector-based cancer gene therapy, the proposed strategy employs non-viral gene delivery using biodegradable polymeric vectors, a platform well established in the applicant’s laboratory.
To overcome drug resistance commonly observed in treating pediatric brain tumors, this approach employs a combined therapy by co-delivering non-viral engineered stem cells with nanoparticles containing chemotherapeutic drugs, which has been found to enhance the responsiveness of pediatric brain tumor cells to gene therapy.
The outcomes of the proposed interdisciplinary approach may advance care for DIPG in ways that would not be possible using conventional treatment paradigms. This will lead to improved survival for patients of DIPG, one of the most deadly forms of pediatric brain cancer and may substantially reduce the associated socioeconomical burden on our society. While the proposed work will initially focus on DIPG as a model disease, the proposed strategy to enhance targeting and treating cancer metastasis may be adapted for treating a broad range of other cancer types as well.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.