Anatoly Nikolaev, MD, PhD

Cleveland Clinic Florida Research and Innovation Center - Radiation Oncology, CITI, FRIC

Pediatric Brain Cancer

Pediatric Pilot Grant

Evaluation of the therapeutic potential of mutant p53 targeting combined with radiation therapy in animal models of pediatric diffuse midline gliomas (DIPG)

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor, which constitutes about 75% of all brainstem malignancies in children. Approximately 350-400 new cases of DIPG are diagnosed each year in the US. The tumor usually affects the children 3-10 years of age. The common presenting symptoms include double vision, loss of balance, unilateral weakness, headaches, and nausea/vomiting. These symptoms progress very quickly. The prognosis is dismal, and survival less than 12 months. DIPG is commonly diagnosed by MRI, biopsy not necessary. The tumor cells diffusely infiltrate the part of the brain called the brainstem. Since the brainstem contains all essential functions including heart rate and breathing controls, surgery is not an option. The effective treatments for DIPG remain elusive. Radiation is a palliative treatment option for DIPG. It provides only a temporary symptomatic relief, without improving survival. On the molecular level, the two most frequently mutated genes in DIPG are histone H3 and tumor suppressor TP53. Histone H3 is a protein involved in packaging of our DNA into a structure called chromatin, while p53 tumor suppressor protein plays a key role blocking cancer progression. Up to 75% of DIPG tumors have mutations in TP53 tumor suppressor gene. The normal function of p53 tumor suppressor is to identify cancerous cells, and to kill them, by triggering a type of cancer cell death called apoptosis. Mutations in TP53 gene in DIPG make p53 tumor suppressor protein inactive, thus allowing cancer cells to escape a strict surveillance by p53. These p53-inactivating mutations had been linked to reduced survival and poor response to treatment with standard radiation therapy in DIPG patients. Restoration of normal p53 function, on the other hand, causes tumor regression without affecting normal tissues. Tolistat-1, and its derivative Tolistat-23, are novel mutant p53-targeting experimental drugs developed at Cleveland Clinic Florida Research and Innovation Center. Our pre-clinical data described in this application indicate that mutant p53 targeting with these novel therapeutic agents increase the sensitivity of DIPG tumor cells to radiation treatment by potentiating tumor cell death. Our hypothesis is that Tolistat-23, when combined with the standard radiation treatment, may improve the efficacy of therapeutic radiation treatment in animal models of DIPG. To determine the therapeutic benefit of combining Tolistat-23 with radiation treatment, we propose to evaluate the outcomes of tumor growth inhibition and survival in animal models of pediatric DIPG. This work may lead to clinical trials investigating the therapeutic efficacy of Tolistat-23 in combination with radiation for pediatric DIPG and other high-grade pediatric gliomas.

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