The Tabori lab is focused on combining biological and translational research in pediatric oncology. Specifically, we are interested in studying mechanisms underlying brain tumor immortality and recurrence in the context of predisposition to cancer. Currently our group is studying 3 major areas related to this concept:
1) Telomere maintenance and cancer recurrence. Using a stepwise approach, we explored the prognostic role of telomere maintenance in pediatric brain tumors. Initially, we have shown that lack of telomere maintenance is involved in the unique property of spontaneous growth arrest seen in pediatric low grade gliomas (Neoplasia 2006) and that telomerase is a significant biological risk factor in pediatric ependymomas (J Clin Oncol 2006, Brit J Cancer 2008). As a second step, we were able to demonstrate that telomerase, the enzyme which maintains telomeres, is active only in the tumor initiating cell (TIC) subpopulation of pediatric gliomas and telomerase inhibition causes growth arrest in glioma TIC cell lines. In contrast, normal stem cells lack telomerase and are insensitive to telomerase inhibition. Finally, telomerase inhibition results in irreversible loss of self-renewal capabilities of TIC in glioma and neuroblastoma in vitro and in vivo (termed stem cell exhaustion, Clin Cancer Res 2011). Importantly, we have identified that a unique methylation of the hTERT promoter tert hypermethylated Oncological Region (THOR) is a cancer signature with immense clinical implications. This work (Lancet Oncology 2014) resulted in a patent and commercialization efforts by the Hospital for Sick Children and MaRS innovation in Toronto. We are currently exploring the causes of this phenomenon and the consequences of THOR in common adult cancers.
- The use of THOR as a diagnostic tool to differentiate between benign and malignant tumors.
- THOR as a prognostic marker on a variety of cancers.
- THOR to find circulating cancer cells in body fluids.
- THOR as a therapeutic target in cancer.
2) Cancer predisposition syndromes. Germline predisposion to childhood brain tumors are a significant part of our research endeavors since I strongly believe that one can learn from germline alterations about somatic tumor events and from somatic tumor mutations on predisposition to cancer (Ying and yang of Cancer Genetics). Furthermore, these involve genomic instability, tumor immortality and are highly associated with telomere biology. As a novel approach to cancer predisposition, wepublished a new method to predict tumor initiation in patients with germline mutations in TP53 (Cancer Res 2007, Cancer Res 2008). We then explored the Ying and Yang of cancer genetics in mutations in TP53 ( germline: PNAS 2008, choroid plexus tumors J Clin Oncol 2010 and clin Cancer Res 2014 and medulloblastoma: J Clin Oncol 2010, J Clin Oncol 2013).
We have established the international consortium of Biallelic mismatch repair deficiency (BMMRD) which uncovered clinical and biological implications of children with biallelic mismatch repair deficiency syndrome (EJC 2014). We have uncovered that bMMRD cancers have the highest mutation load in humans (Ultrahypermutant tumors, Nature Genet 2015) and a mutation signature that can be traced to the germline. These highly collaborative research endeavors are ongoing and result in a wider understanding of main concepts in cancer and clinical targeted therapies for these children.
Current work in the consortium include:
- Determination of the tumor spectrum and risk stratification in individuals with bMMRD.
- Establishment of diagnostic tools and molecular understanding of the events leading to the early and aggressive bMMRD cancers.
- Validation and implementation of international surveillance protocol for early cancer detection in bMMRD.
- Determination of the genetic consequences of ultrahypermutation on the cancer genome and transcriptome.
- Building animal models to study the syndrome and to uncover novel therapies to these cancers and specifically:
- Development of drugs to prevent cancer initiation in bMMRD.
- Development of clinical trials for bMMRD related cancers.
3) Pediatric gliomas. Pediatric low grade gliomas (PLGG) are my clinical and translational passion. This is the most common childhood brain tumor and has unique biological characteristics ranging from spontaneous growth arrest to malignant transformation. We were the first to demonstrate the role of replicative senescence in PLGG and to utilize it as a prognostic factor for PLGG (Neoplasia, 2006). We then initiated and lead a multi-disciplinary Canadian low grade glioma task force which incorporates clinical prospective trials, long term outcome studies and basic science questions. All of these are done in collaboration with the other 17 pediatric cancer centres in Canada under our leadership.
We currently have the largest PLGG clinical-pathological database in the world which includes more than 1000 patients and tumours. We have utilized this Canadian effort in a series of 19 papers to demonstrate the following:
- Clinical observations:
- defined the clinical and epidemiological role of PLGG located in the optic pathway, brainstem and spinal cord; each with its unique clinical outcome;
- defined the role of surgery, chemotherapy and radiation therapy in these tumors; specifically we have shown that radiation is not superior to other modalities and should be avoided if possible to these children;
- demonstrated that second line chemotherapy is as efficacious as first line in this unique group of tumours; a fact that relates to oncogene induced senescence.
5) With funding from OICR, we were able to construct 2 prospective trans-Canadian and international clinical trials for PLGG. These are the ONLY prospective clinical trials which collect biological tissues (J Clin Oncol 2013).
6) Together with Dr Nada Jabado from Montreal, we were one of the first to demonstrate that PLGGs possess the unique BRAF duplication (Brit Journal Cancer, 2008). We then extended our findings to demonstrate that this results in oncogene induced senescence and favorable outcome for these patients (Clin Cancer Res, 2011, Jacob et al Clin Cancer Res, 2011). We also uncovered the genetic events leading to transformation of PLGG (J clin Oncol 2015).
7) With funding from the Pediatric Brain Tumor Foundation USA, we are currently finalizing results from a long term outcome study looking at host and tumour determinants of neurocognitive and functional status of PLGG survivors.
8) As a result of our work, we currently serve as a Canadian and international reference center for biology and clinical testing of PLGG and are leading a clinical trial with targeted BRAF V600E inhibitor.
We are currently embarking on a nambitious project in which we will profile for the first time all molecular alterations in more than 1000 PLGG with more than 30 years of follow up. We will then determine the effect of genetic alterations on clinical outcome and will validate these findings with large centers in the US and the world.
Over the next few years our aims are to transform observations in our 3 areas of research to clinical implications for children with brain tumors.