Mark ASK, MD
(Credit: Weill Cornell Medicine)
Diffuse Mittelline Gliomas (DMGS) are a heterogeneous group of (mainly) pediatric tumors that influence the mid -line structures (thalami, medium brain, pons or spinal cord), which are characterized by glia proliferation and infiltrative nature that makes them incomparable by nearby brain savings. Patients usually have a constellation of symptoms due to the tumor location (i.e. contralateral hemiparesis for the thalamus lesion or long tractual signs and the paresis of the cranial nerve for Pontinian) and obstructive hydrocephalus due to the mass effect on the third or fourth ventric.
The diagnosis is based on characteristic imaging features that have been observed in contrast -reinforced MRI. In the case of diagnostic uncertainties, biopsy can be carried out to guide management. In the past, the treatment of DMGs – of which diffuse intrinsic ponting gliomas (DIPGS) are the most common subtype, is stagnated despite significant improvements in other liquid and firm cancer. After the diagnosis, external radiation therapy remained the main support of therapy with significant but short -lived improvements in overall survival.
In the past ten years, however, a revolution has been held in view of the increased security of stereotactic biopsies and the desire that more tissue could be used for preclinical studies. An increased availability of tissue led to an improved understanding of tumor biology and more reliable preclinical models. The improved social understanding of the disease and its consequences led to an increase in financing – both at the federal level and by generous private donors – with the ultimate hope of achieving a meaningful clinical improvement.
Numerous landmarks followed: Mackay and colleagues, for example, sequenced a thousand DMG samples and identified key mutations in connection with a poorer prognosis. A point mutation on Histon H3 was associated with a significantly worse forecast, for example, but had a therapeutic potential in a similar way. The following studies assessed the epigenetic susceptibility of DIPG with current clinical studies that aim to normalize an otherwise aberrant epigenetic landscape.
Umberto Tosi, MD
(Credit: Weill Cornell Medicine)
The explosion in preclinical studies and models led to a parallel increase in clinical studies to improve the DMG forecast. It is important that they were not geared towards a single approach, a therapeutic or a drug; Rather, there were several studies that dealt with various aspects of the complex biology of the DMG. Current clinical studies can remove the current examination efforts and can be separated in four wide groups:
- Direct pharmaceutical tax: In view of the inability of most systemic compounds to easily exceed blood tumor barriers and accumulating from the development of systemic side effects on therapeutic values in the tumor, direct drug emission strategies are based on the cannula implantation of tumor parenchyma, in order to cover high locore region concentrations with minimal systemic exposure and toxicity to reach. The latest clinical studies have shown that this convection approach (CED) for radioactive monoclonal antibodies and histone deacetylase inhibitors have highlighted small molecules for convection-enhanced levy (CED) and the importance of infuse monitoring after childbirth. Further studies are required to determine whether CED can lead to a sensible clinical improvement. The clinical study of the early phase of our group, in which a monoclonal antibody of children with DIPG was given, not only showed the security of this approach, but also led to promising evidence for long -term survivors. In view of these encouraging data, follow-up-up attempts are in development.
- Locorative regional blood-tumor barrier opening: The blood tumor barrier can be opened to maximize the therapeutic accumulation within the tumor. Clinical studies in the early phases evaluate the feasibility of this approach by combining the MRI-guided focus ultrasound in order to open the blood tumor barrier with intra-arterial drug tax, which is promising in preclinical models.
- Oncolytic virus: In view of the failure of most systemic chemotherapy, a new oncolytic virus (DNX-2401) was developed to target DIPG cells and to lead to reduced tumor load through a combination of direct oncolysis, immune activation and synergy. A first clinical study in which this approach was tested in 12 patients showed the general security and a promise for further investigations.
- Car-T therapy: Car-T cells, technical T cells that house a chimerous antigen receptor that leads to their activation with antigen binding, are promising in numerous liquid and firm types of cancer. It is known that a subtype of DMG has a high expression of disialoganglioside GD2. In a recently carried out clinical study, 4 patients with DMG were administered intravenously by anti-GD2 car-T cells, 3 of which were also subjected to intrathecal administration. Overall, this study showed the feasibility of this approach with significant intensive care and neurosurgical support (e.g. the placement of hydrocephalus).
A success story in DipG Discovery and newly discovered optimism comes from the alliance between Philanthropic dollars and translational investigators. A solid correlation between DipG-oriented philanthropy and scientific discovery was observed. Never before has there been such a wealth of therapeutic studies for pediatric patients with DIPG; Renewed hope. A solid example of this partnership is the alliance between Mark Souweidane, MD of the children's brain tumor project and Cristian Rivera Foundation. This is just an example of how this type of partnership has postponed the needle and offered a few children for additional years. Overall, the understanding of the biology of DMGS and its therapeutic weaknesses has changed overall. Hopefully current studies can improve an otherwise irreconcilable forecast.