Advancing Clinical Response Against Glioblastoma: Evaluating SHP1705 CRY2 Activator Efficacy in Preclinical Models and Safety in Phase I Trials.

Background: It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are uniquely essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity. Methods: We analyzed buffy coats isolated from Phase 1 clinical trial subjects' blood to assess any changes to circadian, housekeeping, and blood transcriptome-based biomarkers following SHP1705 treatment. We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employed in vitro and in vivo methods to test the efficacy of SHP1705 against patient-derived GSCs and xenografts in comparison to earlier CRY activator scaffolds. Additionally, we applied a novel-REV-ERB agonist SR29065, which inhibits BMAL1 transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells. Results: SHP1705 is safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published CRY activators. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with the novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs). Conclusions: These demonstrate the efficacy of SHP1705 against GSCs, which pose for GBM patient outcomes. They highlight the potential of novel circadian clock compounds in targeting GBM as single agents or in combination with each other or current standard-of-care. KEY POINTS: SHP1705 is a novel CRY2 activator that has shown success in Phase 1 safety trialsSHP1705 has a significantly improved efficacy against GSCs and GBM PDX tumorsNovel REV-ERB agonist SR29065 and SHP1705 display synergistic effects against GSCs. IMPORTANCE OF THE STUDY: CRY2 is decreased in GBM tissues compared to CRY1 suggesting that promoting CRY2 activity will be an efficacious GBM treatment paradigm. SHP1705, a CRY2 activator that has shown success in Phase 1 safety trials, has significantly improved preclinical efficacy. Novel REV-ERB agonist SR29065 displays synergistic effects against diverse GBM cells.

An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth.

Vestibular schwannoma is a benign neoplasm arising from the Schwann cell sheath of the auditory-vestibular nerve. It most commonly affects both sides in the genetic condition Neurofibromatosis type 2, causing progressive high frequency sensorineural hearing loss. Here, we describe a microsurgical technique and stereotactic coordinates for schwannoma cell grafting in the vestibular nerve region that recapitulates local tumor growth in the cerebellopontine angle and inner auditory canal with resulting hearing loss. Tumor growth was monitored by bioluminescence and MRI in vivo imaging, and hearing assessed by auditory brainstem responses. These techniques, by potentially enabling orthotopic grafting of a variety of cell lines will allow studies on the pathogenesis of tumor-related hearing loss and preclinical drug evaluation, including hearing endpoints, for NF2-related and sporadic schwannomas.

A corrole nanobiologic elicits tissue-activated MRI contrast enhancement and tumor-targeted toxicity.

Water-soluble corroles with inherent fluorescence can form stable self-assemblies with tumor-targeted cell penetration proteins, and have been explored as agents for optical imaging and photosensitization of tumors in pre-clinical studies. However, the limited tissue-depth of excitation wavelengths limits their clinical applicability. To examine their utility in more clinically-relevant imaging and therapeutic modalities, here we have explored the use of corroles as contrast enhancing agents for magnetic resonance imaging (MRI), and evaluated their potential for tumor-selective delivery when encapsulated by a tumor-targeted polypeptide. We have found that a manganese-metallated corrole exhibits significant T1 relaxation shortening and MRI contrast enhancement that is blocked by particle formation in solution but yields considerable MRI contrast after tissue uptake. Cell entry but not low pH enables this. Additionally, the corrole elicited tumor-toxicity through the loss of mitochondrial membrane potential and cytoskeletal breakdown when delivered by the targeted polypeptide. The protein-corrole particle (which we call HerMn) exhibited improved therapeutic efficacy compared to current targeted therapies used in the clinic. Taken together with its tumor-preferential biodistribution, our findings indicate that HerMn can facilitate tumor-targeted toxicity after systemic delivery and tumor-selective MR imaging activatable by internalization.