Updated Research from Dr. Fouladi
Last year’s proposal: we proposed to assess the genomic landscape of children and adults with pineoblastoma and primitive neuroectodermal tumors in general to build on data that have recently been published (Snuderl et al, 2018, Hwang et al, 2018) to demonstrate the unique biological characteristics of these tumors that may help us to improve our treatments and lead to better outcome and survival for young children with these tumors:
1. Conduct whole genome, whole exome, RNA sequencing and methylation profiling of available tumors here at CCHMC and our collaborators at others centers to build on our growing knowledge and understanding of these tumors
2. To develop an international feasibility study with novel agents and approaches for children with pineoblastomas and embryonal tumors in general through the CONNECT Consortium, a 19-member international consortium with sites in the US, Canada, Australia, England, Germany and the Netherlands.
Update on our achievements: In a collaboration led by Dr. Annie Huang at the Hospital for Sick Children in Toronto we recently published data on tumor and clinical findings with all our patients with ETMRs, an infant brain tumor which includes pineoblastomas in July 2019 in Cancer Cell entitled: A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor. Sin-Chan P1, ……1, Fouladi M6, …….., Huang A42.
We have also just submitted a large series of patients with pineoblastomas for publication again in a collaboration with Dr. Annie Huang.
Together with Drs. Sarah Leary and Annie Huang we intend to conduct an international study through the CONNECT consortium for patients with PNET/pineoblastomas/ETMR through the CONNECT consortium in the next year.
Funds from Jaxsen’s Journey will be critical to support this clinical trial.
Here is the summary of the proposed study that we hope will be refined and developed over the next year:
Despite intensive multimodal therapy, 5-year EFS for children with embryonal tumors which include medulloblastomas, pineoblastomas is 54% with multimodal therapy (ACNS0334). Histone deacetylase inhibitors (HDACi) such as vorinostat, have demonstrated promising efficacy in preclinical studies of ATRTs and embryonal tumors and have proven safe and effective when incorporated in the ACNS0334 backbone (PBTC026), leading to 65% 5-year EFS . HDACi prime tumors for more effective checkpoint blockade by activating expression of human endogenous retroviruses and sparking a T-cell mediated immune response through a process called “viral mimickry.” Published preclinical data support the combination of PD-1 inhibitors with HDAC inhibitors in adult and pediatric malignancies, including CNS (Ashley, personal communication). Analysis of ATRT and embryonal tumor specimens has revealed significant intra-tumoral heterogeneity and enrichment for macrophages, T cell, and IFN-G signatures across ATRT subtypes, implicating ineffective anti-tumour response in pathogenesis. Based on these data we propose a feasibility study in children with embryonal tumors to test nivolumab in combination with the PBTC026 backbone and to develop a better understanding of the changes in structure of the immune system and microbiome of children during cancer therapy.
The primary objective is to test the regimen’s feasibility and safety. Secondary objectives are to assess early efficacy and explore changes in naïve, effector, and memory T-cell compartments, in T-cell receptor clonality and in gut commensal microbial flora during multimodal therapy.
Funding request: for the conduct of the study
Accrual: 1-2 patients/month for 10-12 pts through CONNECT. Correlative studies will be completed within two years. BMS is supportive of study.