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Principal Investigators

Jann Sakaria, Mayo Clinic
Evanthia Galanis, Mayo Clinic
Antonio Omuro, Yale University
Ranjit Bindra, Yale University

Title

Center of Innovation for Brain Tumor Therapeutics

Project Information

Project 1 - Alkylating chemotherapies are part of the backbone of standard-of-care therapy in newly diagnosed disease, and they are also used in the recurrent setting. We and others have demonstrated that these agents each induce unique spectra of DNA damage, which engage specific DNA damage response (DDR) pathways depending on the status of key DNA repair pathways. The most commonly used agents are temozolomide (TMZ), a monofunctional alkylator that induces methyl-adducts on discrete DNA base sites, and lomustine and carmustine, which are bifunctional alkylators that induce both mono-adducts and DNA cross-links. The different DNA lesions induced by these and other alkylating therapies trigger distinct DNA damage responses critically modulated by ataxia-telangiectasia mutated (ATM) and ATM/Rad3-related (ATR) kinases, which orchestrate the cellular response to a broad array of genotoxic insults. Over the past few years, we have collaborated with the NCI Cancer Therapy Evaluation Program and multiple pharmaceutical companies (AstraZeneca, Vertex, Merck KGaA, Bayer) to evaluate multiple highly brain penetrant ATM and ATR inhibitors in combination with radiation therapy and alkylating chemotherapies. Our preliminary data demonstrate robust synergy between TMZ and ATR inhibitors, specifically in GBM models lacking. Mechanistically, unrepaired O6-methyguanine lesions induced by TMZ cause replication stress and activation of the ATR signaling axis. In contrast, synergistic interactions of ATR inhibitors with lomustine were independent of MGMT status, which reflects a distinct set of alkylation lesions that are relatively unaffected by MGMT repair activity. Overall, our extensive preliminary data support the fundamental scientific premise that monofunctional and bifunctional alkylator therapies trigger distinct functional and temporal activation of DNA damage response pathways governed by ATM and ATR. Understanding these relationships can be used to define optimal combinations of ATR or ATM inhibitors with various alkylating agents for GBM.

Project 2 - Disruption of tumor suppressor p53 function is the most common alteration in cancer and results in dysregulation of DNA repair following genotoxic insults. Use of small molecule inhibitors blocking the interaction of p53 with murine double minute 2 (MDM2) prevents MDM2-mediated degradation of p53 and is the most clinically advanced strategy to target this critical DNA damage response pathway. In this project, we introduce the highly potent MDM2 inhibitor BI-907828 as a novel therapeutic approach against glioblastoma (GBM). This best-in-class MDM2 inhibitor is highly potent in vitro in GBM PDXs at single-digit nanomolar concentrations. BI-907828 monotherapy has significant anti-tumor activity against orthotopic GBM PDXs with corresponding robust evidence of on-target pharmacodynamic drug effects – stabilization of p53 and increased p53-mediated transcription of pro-apoptotic genes. Further, combined therapy with BI-907828 and radiation markedly enhances induction of pro-apoptotic genes in both the extrinsic and intrinsic apoptotic pathway, and combined radiation/BI-907828 therapy in orthotopic PDXs results in profound extension of animal survival in two GBM PDXs. This activity in orthotopic PDX models known to have an intact blood brain barrier is especially interesting since BI-907828 has relatively limited distribution into normal brain. In contrast to modulation of mitogenic signaling or many other DNA repair targets, which require sustained, high-level suppression of optimal effects, MDM2 tightly regulates p53 stability in a negative feedback loop. Thus, we hypothesize that even short-term inhibition of MDM2 activity can lead to increased expression of p53 sufficient to activate pro-apoptotic effects of p53. Defining the differences in pharmacologic effect when targeting distinct types of regulatory circuits (e.g., positively cooperative signaling networks vs. negative feedback transcriptional networks) represents a key innovation of the planned project. The specific Aims of the project are: Aim 1: Develop a PK→PD→efficacy model for BI-907828 monotherapy in GBM PDXs Aim 2: Conduct a phase 0 trial to evaluate the distribution and pharmacodynamics of BI-907828 in GBM Aim 3: Determine the tolerability of BI-907828 combined with radiation in patients with newly diagnosed GBM Aim 4: Evaluate combinatorial strategies for BI-907828 with other anticancer therapies for GBM