# US 12,594,293 B2 · Use of 6-thio-dG to treat therapy-resistant telomerasepositive pediatric brain tumors

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- Number: US 12,594,293 B2
- Document ID: US12594293B2
- Status: Granted
- Kind: B2
- Application number: 18/511,417
- Filed: 2023-11-16
- Published: 2024-06-13
- Granted: 2026-04-07
- Earliest claimed: 2018-03-22
- Assignees: Board of Regents, The University of Texas System; Children's Hospital Medical Center
- Applicants: The Board of Regents of The University of Texas System; Children's Hospital Medical Center
- Inventors: Jerry Shay; Rachid Drissi
- Web page: https://patentgrep.com/patent/US12594293B2

## CPC

- A61K 31/708: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
- A61P 35/04: specific for metastasis
- A61P 35/00: Antineoplastic agents
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG) and high-risk medulloblastoma (MB). It has shown that DIPG, HGG and MB frequently express telomerase activity. It is now shown that the telomerase-dependent incorporation of 6-thio-2′deoxyguanosine (6-thio-dG), a telomerase substrate precursor analog, into telomeres leads to telomere dysfunction-induced foci (TIFs) along with extensive genomic DNA damage, cell growth inhibition and cell death of primary stem-like cells derived from patients with DIPG, HGG and MB. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2/M arrest. In vivo, treatment of mice bearing MB xenografts with 6-thio-dG delays tumor growth, increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, these findings suggest that 6-thio-dG is a promising approach to treat therapy-resistant telomerase-positive pediatric brain tumors.

## Claims

### Claim 1

A method of treating a diffuse intrinsic pontine glioma (DIPG) in a pediatric subject, comprising administering 6-thio-2′deoxyguanosine (6-thio-dG) to a subject in need thereof, thereby treating pediatric brain cancer.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject's is age 1-21 years of age.

### Claim 3 (depends on 1)

The method of claim 1, wherein the DIPG is drug resistant.

### Claim 4 (depends on 1)

The method of claim 1, wherein the DIPG has telomerase activity.

### Claim 5 (depends on 1)

The method of claim 1, wherein 6-thio-dG induces in vivo telomere dysfunction-induced foci (TIFs), apoptosis, and an inhibition of tumor growth.

### Claim 6 (depends on 1)

The method of claim 1, wherein 6-thio-dG is administered in combination or sequentially with a chemotherapeutic agent.

### Claim 7 (depends on 1)

The method of claim 1, wherein 6-thio-dG is administered in combination with an immune checkpoint inhibitor.

### Claim 8 (depends on 1)

The method of claim 1, further comprising the step of assessing telomerase activity in a brain cancer cell from said subject.

### Claim 9 (depends on 7)

The method of claim 7, wherein the immune checkpoint inhibitor is an anti-PD-L1 or PD-1 antibody.