Viral therapy research
Over the past 20 years, the Lang laboratory has played a significant role in the development and bench-to-bedside translation of Delta-24-RGD, a novel replication-competent, tumor selective oncolytic adenovirus. Our laboratory has demonstrated the efficacy of this virus in treating gliomas, in both preclinical glioma models and in human clinical trials. Specifically, we have shown that Delta-24-RGD is able to directly kill tumors by infecting and replicating in glioma cells, and ultimately lysing them. Equally important, we have recently provided evidence that Delta-24-RGD induces indirect cell death by activating a tumor-specific, cytotoxic T cell immune-mediated response. These preclinical studies led to a Phase I clinical trial of treating recurrent glioblastoma patients with Delta-24-RGD. Current research focuses on understanding the immune effects of Deta-24-RGD through studies using an immune-competent, adenovirus-permissive hamster for which we have developed a syngeneic orthotopic glioma model system.
Mesenchymal stem cell research
The Lang lab was the first to show that bone marrow human mesenchymal stem cells (BM-hMSCs) migrate toward gliomas after intracranial delivery, and even more notably, localize to human gliomas after systemic intra-arterial delivery. We were also the first to show that this homing capability can be exploited for therapeutic benefit, as BM-hMSCs loaded with Delta-24-RGD successfully eradicate gliomas in vivo. Current research involves understanding the homing mechanisms of BM-hMSCs and exploring the applicant of BM-hMSCs carrying Delta-24-RGD using models that mimic clinical scenarios for the treatment of GBMs, such as up front treatment and post-resection.
Furthermore, we have shown that exosomes derived from cultured BM-hMSCs can be used as delivery vehicles for therapeutic genes, particularly small interfering RNAs and microRNAs. Current research focuses on identifying the optimal microRNAs that work alone or in combination to eradicate gliomas across subtypes.
The Lang Lab has also identified endogenous mesenchymal stem cells within human gliomas, and showed that they enhance the proliferation and tumorigenicity of glioma stem cells. Much of this research has been made possible by the establishment of a large collection of molecularly characterized glioma stem cells generated from human brain tumor specimens and by using enhanced high throughput animal models for testing anti-glioma agents. These cells and their molecular information has been made available to all researchers via a Material Transfer Agreement that maintains the quality and distribution of the cells.
p53 mutation research
The p53 gene is now recognized as a critical tumor suppressor in human cancer. Research led by Frederick Lang, M.D., showed that the p53 gene is also mutated or dysregulated in low grade astrocytomas (WHO grade I astrocytomas) and anaplastic astrocytomas (WHO grade III astrocytoma), a finding that contributed not only to the concept that p53 inactivation was an early event in gliomagenesis, but also to the now-accepted concept of secondary gliomas. This work led to a pioneering clinical trial of the first p53 gene therapy in patients and the first “treat-resect-treat” strategy in a brain tumor clinical trial. Ultimately, the trial results led to the development of viral therapies.
5P50 CA127001 (SPORE in Brain Cancer)
R01 CA214749 (MSC-derived exosomes and microRNA in glioma therapy)
R01 CA247970 (A Novel Adenoviral-Permissive, Immunocompetent Hamster Model to evaluate Oncolytic Adenoviral Therapy for Glioblastoma)