- Document Number:
20240189336
- Appl. No:
18/511417
- Application Filed:
November 16, 2023
- نبذة مختصرة :
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.
- Assignees:
The Board of Regents of The University of Texas System (Austin, TX, US), Children's Hospital Medical Center (Cincinnati, OH, US)
- Claim:
1. A method of treating a brain cancer in a pediatric subject, comprising administering a telomerase substrate precursor analog to a subject in need thereof, thereby treating pediatric brain cancer.
- Claim:
2. The method of claim 1, wherein the subject's is age 1-21, 1-18 or 1-14.
- Claim:
3. The method of claim 1, wherein the pediatric brain cancer is drug resistant.
- Claim:
4. The method of claim 1, wherein the pediatric brain cancer is diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), or high-risk medulloblastoma (MB).
- Claim:
5. The method of claim 1, wherein the brain cancer has telomerase activity.
- Claim:
6. The method of claim 1, wherein the telomerase substrate precursor analog is 6-thio-2′deoxyguanosine (6-thio-dG).
- Claim:
7. The method of claim 6, wherein 6-thio-dG induces in vivo telomere dysfunction-induced foci (TIFs), apoptosis, and an inhibition of tumor growth.
- Claim:
8. The method of claim 1, wherein the telomerase substrate precursor analog is administered in combination or sequentially with an immunotherapeutic agent, a targeted drug, an epigenetic modifier, a chemotherapeutic agent, radiotherapy, or any combination thereof.
- Claim:
9. The method of claim 1, wherein the telomerase substrate precursor analog is administered in combination with an immune checkpoint inhibitor, such as an anti-PD-L1 or PD-1 antibody.
- Claim:
10. The method of claim 1, further comprising the step of assessing telomerase activity in a brain cancer cell from said subject.
- Claim:
11. A method of inducting G2/M cell cycle arrest in a cancer cell comprising contacting the cell with a telomerase substrate precursor analog and a telomerase inhibitor.
- Claim:
12. The method of claim 11, wherein the cancer cell is a brain cancer cell.
- Claim:
13. The method of claim 12, wherein the brain cancer cell is drug resistant.
- Claim:
14. The method of claim 11, wherein the brain cancer cells is diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), or high-risk medulloblastoma (MB).
- Claim:
15. The method of claim 11, wherein the cancer cell exhibits telomerase activity.
- Claim:
16. The method of claim 11, wherein the telomerase substrate precursor analog is 6-thio-2′deoxyguanosine (6-thio-dG).
- Claim:
17. The method of claim 16, wherein 6-thio-dG induces in vivo telomere dysfunction-induced foci (TIFs), apoptosis, and an inhibition of tumor growth.
- Claim:
18. The method of claim 11, wherein the telomerase substrate precursor analog is administered in combination or sequentially with an immunotherapeutic agent, a targeted drug, an epigenetic modifier, a chemotherapeutic agent, radiotherapy, or any combination thereof.
- Claim:
19. The method of claim 11, further comprising the step of assessing telomerase activity in said cancer cell.
- Claim:
20. The method of claim 11, wherein the cell cycle arrest induces the accumulation of genomic DNA damage
- Current International Class:
61; 61; 61
- الرقم المعرف:
edspap.20240189336
Processing Request
No Comments.