A broad body of data suggests that small molecule antagonists of the bHLH transcription factor Olig2 would have therapeutic value for both pediatric and adult astrocytomas. However transcription factors are generally considered to be unattractive targets for drug development because their interactions with DNA and with co-regulator proteins involve large and complex surface area contacts. A second major challenge - generic to any drug development project involving CNS cancers - is the blood/brain barrier. The broad goal of this project is to develop a small molecule Inhibitor of Olig2 that can cross the blood/brain barrier. Our two specific aims are to adapt a pair of innovative new methods towards this goal.
Aim one is to use """"""""stapled peptide"""""""" chemistry to generate small molecule alpha-helical mimetics that can disrupt the interaction between Olig2 and essential co-regulator proteins.
Aim two is to use MALDI mass spectrometry imaging for direct imaging of these stapled peptide mimetics within the interstitial spaces ofthe brain at a resolution of 50 um (soon to be 10 um). Our study plan will merge these two methodologies into an iterative protocol for modification of lead compounds into potent, highly specific antagonists of Olig2 with good blood/brain barrier penetrance. The study plan will be carried out by a team with skill sets in three separate fields: The Stiles lab has credentials in the area of transcription factors and neural development. Co-investigator Loren Walensky is an authority on stapled peptide chemistry. Co-investigator Nathalie Agar provides the essential expertise in MALDI mass spectrometry imaging. The study plan for this project will benefit from economies of scale enabled by the Innovative Neuropathology Core. Mutually beneficial collaborative interactions with the investigators on Project One and Project Three will insure that the ultimate contributions of this program to the field of astrocytoma research exceeds the contributions ofthe individual project components.
Initially as tool compounds and in the fullness of time as therapeutics, the Olig2 antagonists we envision could impact research and treatment of an underserved disease - namely pediatric low-grade astrocytoma (PLGA). Moreover, small molecule inhibitors of Olig2 could serve as targeted therapeutics for a wide range of adult gliomas as well.
|Pak, Ekaterina; Segal, Rosalind A (2016) Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy. Dev Cell 38:333-44|
|Bandopadhayay, Pratiti; Ramkissoon, Lori A; Jain, Payal et al. (2016) MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48:273-82|
|Yuzugullu, Haluk; Von, Thanh; Thorpe, Lauren M et al. (2016) NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov 2:16030|
|Stevens, Mark M; Maire, Cecile L; Chou, Nigel et al. (2016) Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate. Nat Biotechnol 34:1161-1167|
|Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane et al. (2016) Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas. Clin Cancer Res 22:1185-96|
|Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6|
|Filbin, Mariella G; Segal, Rosalind A (2015) How neuronal activity regulates glioma cell proliferation. Neuro Oncol 17:1543-4|
|Brastianos, Priscilla K; Carter, Scott L; Santagata, Sandro et al. (2015) Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov 5:1164-77|
|Zhou, Pengcheng; Erfani, Sonia; Liu, Zeyi et al. (2015) CD151-Î±3Î²1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion. Oncotarget 6:29675-93|
|Zhao, Xuesong; Ponomaryov, Tatyana; Ornell, Kimberly J et al. (2015) RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer Res 75:3623-35|
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