Drissi Lab

We used a novel strategy to induce telomere damage in telomerase-positive and therapy-resistant pediatric brain tumors. we showed that the telomerase-dependent incorporation of 6-thio-dG, a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction–induced foci (TIF) along with extensive genomic DNA damage. Our findings suggested that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors.

• Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors

We identified BMI-1 as a therapeutic target in Diffuse Intrinsic Pontine Glioma (DIPG). The role of BMI-1 in DIPG was largely unknown. We showed that BMI-1 is highly expressed in tumor tissue samples of DIPG patients and in patient-derived cancer stem-like cells. Our data validated BMI-1 as a potential therapeutic target to treat children with DIPG. Furthermore, our findings indicated that BMI-1 modulation is associated with mitotic abnormalities, impaired DNA damage response, and cell death, supporting the combination of BMI-1 modulation and radiation as a promising novel therapy for children with DIPG.

• BMI-1 is a Potential Therapeutic Target in Diffuse Intrinsic Pontine Glioma

Our radiogenomics study was the first one to apply an approach combining magnetic resonance imaging (MRI) features and genomics in patients with DIPG in order to (1) investigate relationships between MRI characteristics at post-radiotherapy time points with tumor molecular profiles identified through extensive genome-wide sequencing analyses, and (2) further explore the radiographic, clinical, and biological heterogeneity of this disease. This study has begun elucidating relationships between post-radiotherapy radiographic response with DIPG molecular profiles, revealing radiogenomically distinct subgroups with unique clinical trajectories and therapeutic targets.

• A Pilot Radiogenomic Study of DIPG Reveals Distinct Subgroups With Unique Clinical Trajectories and Therapeutic Targets

The Drissi Laboratory is leading or co-leading projects in collaboration with major groups in the field of pediatric brain tumors focusing on the understanding of high-risk pediatric brain tumor biology and the mechanisms of synergy and resistance in these malignancies in order to identify molecular therapeutic targets and develop new treatment paradigms. We evaluated and targeted telomerase activity and expression in children with central nervous (CNS) malignancies using a direct inhibitor of telomerase. Our results indicated that telomerase inhibition is observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

• A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent or Refractory Central Nervous System Malignancies: A Pediatric Brain Tumor Consortium Study

Dr. Drissi evaluated the molecular relationship between telomere dysfunction and DNA damage signaling pathway. He demonstrated that ATM activation is a sensitive and a specific marker of telomere dysfunction in aging primary human fibroblasts. He also demonstrated that short telomeres induce chromatin structure changes that limit access of activated ATM to its downstream targets on the chromatin, thereby providing a potential explanation for the increased radiation sensitivity seen with telomere shortening.

• Disappearance of the Telomere Dysfunction-Induced Stress Response in Fully Senescent Cells
• Telomere Shortening Alters the Kinetics of the DNA Damage Response After Ionizing Radiation in Human Cells