Research in Dr. Sarkaria's Translational Neuro-Oncology Laboratory has several focus areas.
One promising novel therapeutic approach uses antibody-drug conjugates (ADC). ADCs combine monoclonal antibodies and cytotoxic payloads to target specific cell receptors such as epidermal growth factor receptor (EGFR). However, ADCs, along with other large biomolecules, have historically failed in clinical trials due to poor drug distribution beyond the blood-brain barrier. To address this shortcoming, our lab is focusing on multiple delivery strategies to open or bypass the blood-brain barrier, including convection-enhanced delivery, receptor-mediated transcytosis, brain-homing aptamer technology and focused ultrasound.
P53 regulates many cellular processes, including DNA repair, cell cycle progression, apoptosis and metabolism. Cellular levels of p53 are tightly controlled by MDM2, which ubiquitinates and targets p53 for degradation. A majority of IDH-wildtype glioblastomas are p53-wildtype and thus inactivate p53 through other mechanisms, including MDM2 amplification and CDKN2A/B deletion. MDM2 inhibitors are a worthwhile therapeutic strategy in glioblastoma and have been shown to radiosensitize glioblastoma tumors.
Our current work focuses on preclinical evaluation of two MDM2 inhibitors that are in early-stage glioblastoma trials (KRT-232, BI-907828). Our work focuses on evaluating the mechanisms of MDM2 inhibitor-mediated radiosensitization, identification of novel molecular biomarkers predicting response and resistance mechanisms, evaluation of CNS drug delivery, and pharmacokinetics.
DNA damage response inhibitors
Given the clinically significant benefit but limited long-term local control derived from chemoradiation, there is compelling rationale to develop strategies to enhance the efficacy of chemoradiation for glioblastoma (GBM). Dysregulation of DNA damage response (DDR) pathways in cancer cells underlies hypersensitivity or resistance to commonly used genotoxic therapies.
Our laboratory is focused on identifying DDR inhibitors that can augment chemoradiation therapy without enhancing normal tissue injuries. In partnership with pharmaceutical companies, we're involved in the preclinical evaluation of novel pharmacological inhibitors of the DDR (including PARP, ATM, ATR and DNA-PKcs) in combination with radiation and alkylating chemotherapies. A key focus is developing integrated PKPD and efficacy models in glioblastoma PDXs and defining tumor-specific biomarkers of response and synthetic lethal interactions that can be exploited for therapeutic gains.
Pharmaceutical industry collaborations
Our diverse collection of clinically relevant glioblastoma PDX models represents an invaluable resource that is also available to the pharmaceutical industry for novel therapeutic evaluations. Our group has more than 20 years of extensive expertise in study designs aimed at examining efficacy, tolerability and pharmacokinetic-pharmacodynamic profiles, resulting in 58 working relationships with industry to date (26 service contracts, 32 collaborations). Through these collaborations, we aim to expand the use of our highly characterized GBM PDX panel with the end goal of curing glioblastoma.