Reference Detail

Ref Type

Journal Article

PMID

(29769307)

Authors

Karlin J, Allen J, Ahmad SF, Hughes G, Sheridan V, Odedra R, Farrington P, Cadogan EB, Riches LC, Garcia-Trinidad A, Thomason AG, Patel B, Vincent J, Lau A, Pike KG, Hunt TA, Sule A, Valerie NCK, Biddlestone-Thorpe L, Kahn J, Beckta JM, Mukhopadhyay N, Barlaam B, Degorce SL, Kettle J, Colclough N, Wilson J, Smith A, Barrett IP, Zheng L, Zhang T, Wang Y, Chen K, Pass M, Durant ST, Valerie K

Title

Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	17	8	2018 08	1637-1647	Mol Cancer Ther

URL

Abstract Text

Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells in vitro AZ32, with enhanced blood-brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, because many GBMs have defective p53 signaling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses. Mol Cancer Ther; 17(8); 1637-47. ©2018 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AZ31	AZ31	0	0
AZ32	AZ32	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZ31		AZ-31\|AZ 31	ATM Inhibitor 13	AZ31 is an ATM inhibitor, potentially increasing radiosensitization of tumor cells (PMID: 29769307).
AZ32		AZ-32\|AZ 32	ATM Inhibitor 13	AZ32 is an ATM inhibitor, potentially increasing apoptosis and radiosensitization of tumors (PMID: 29769307).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 C238S	high grade glioma	sensitive	AZ32 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in malignant glioma cells harboring TP53 C238S in culture, resulting in a greater decrease in cell survival compared to radiation treatment alone (PMID: 29769307).	29769307
TP53 wild-type	colon carcinoma	sensitive	AZ32 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in TP53 wild-type colon carcinoma cells compared to radiotherapy alone in culture, and wild-type TP53 cells were more sensitive to the treatment combination than TP53 mutant cells (PMID: 29769307).	29769307
TP53 wild-type	high grade glioma	predicted - sensitive	AZ32 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in TP53 wild-type malignant glioma cell lines in culture, however, the effect was smaller compared to the effects in TP53 mutant cell lines (PMID: 29769307).	29769307
TP53 dec exp	high grade glioma	sensitive	AZ32 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, shRNA knock-down of TP53 in malignant glioma cells enhanced sensitivity to the combination of AZ32 and radiation compared to TP53 wild-type cells in culture, and resulted in a greater decrease in cell survival and increased mitotic failure compared to either treatment treatment alone (PMID: 29769307).	29769307
TP53 mutant	high grade glioma	predicted - sensitive	KU-60019 + Radiotherapy	Preclinical	Actionable	In a preclinical study, KU-60019 treatment increased sensitivity to radiotherapy in TP53-mutant mouse glioma cells in culture, and the combination prolonged survival in syngeneic intracranial tumor models compared to radiation alone (PMID: 29769307).	29769307
TP53 D281G	high grade glioma	sensitive	AZ32 + Radiotherapy	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in malignant glioma cells harboring TP53 D281G, resulting in significantly increased survival (P=0.0015) in intracranial cell line xenograft models compared to radiotherapy alone (PMID: 29769307).	29769307
TP53 R175H	high grade glioma	sensitive	AZ32 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in malignant glioma cells harboring TP53 R175H in culture, resulting in a greater decrease in cell survival and increased mitotic failure compared to radiation treatment alone (PMID: 29769307).	29769307
TP53 mutant	high grade glioma	no benefit	AZ31 + Radiotherapy	Preclinical	Actionable	In a preclinical study, AZ31 treatment increased sensitivity to radiotherapy in TP53-mutant mouse glioma cells in culture, but failed to radiosensitize tumors in syngeneic mouse models due to poor blood-brain barrier permeability (PMID: 29769307).	29769307
TP53 R248W	colon carcinoma	predicted - sensitive	AZ32 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in colon carcinoma cells harboring TP53 R248W compared to radiotherapy alone in culture, resulting in increased mitotic catastrophe; however, wild-type TP53 cells were more sensitive to the treatment combination than TP53 R248W mutant cells (PMID: 29769307).	29769307
TP53 M237I	high grade glioma	sensitive	AZ32 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in malignant glioma cells harboring TP53 M237I in culture, resulting in a greater decrease in cell survival compared to radiation treatment alone (PMID: 29769307).	29769307
TP53 mutant	high grade glioma	predicted - sensitive	AZ32 + Radiotherapy	Preclinical	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy in TP53 mutant mouse glioma cells, resulting in reduced cell survival and impaired DNA damage response in culture, and prolonged survival and significantly increased apoptosis of tumor cells compared to normal brain cells (p<0.01) in syngeneic intracranial tumor models (PMID: 29769307).	29769307
TP53 M237I	high grade glioma	sensitive	KU-60019 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, KU-60019 treatment increased sensitivity to radiotherapy in malignant glioma cells harboring TP53 M237I in culture, resulting in a greater decrease in cell survival compared to radiation treatment alone (PMID: 29769307).	29769307
TP53 Q331*	lung non-small cell carcinoma	sensitive	AZ32 + Radiotherapy	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AZ32 treatment increased sensitivity to radiotherapy and demonstrated increased tumor growth inhibition and prolonged survival compared to radiation alone in an intracranial cell line xenograft model of non-small cell lung cancer brain metastasis harboring TP53 Q331* (PMID: 29769307).	29769307