Discovery of a Molecule That Inhibits Tumor Cell DNA Repair

Overview of Pediatric Cancer Treatment Challenges

Despite significant advancements in cancer treatment, the cure rates for pediatric and adult solid tumors remain suboptimal. A common issue is the development of resistance to chemotherapy due to mutations within tumors, which complicates effective treatment.

PGBD5 Enzyme and Its Role in Pediatric Cancers

A recent landmark study published in *Science Translational Medicine* highlighted the enzyme PGBD5, found in a majority of pediatric cancer types, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma. PGBD5 acts as a DNA transposase, an enzyme that cuts and relocates DNA within the genome. Notably, the PGDB5 gene, responsible for this enzyme, is generally inactive in healthy adult and child cells. The researchers hypothesized that tumor cells expressing PGDB5 rely on a functioning DNA repair system for survival; if this system fails, it leads to DNA damage and subsequent cell death.

Identifying a Potential Treatment: AZD6738

In their research, the scientists screened for small molecules capable of hindering DNA repair mechanisms and identified AZD6738. This molecule inhibits ATR, a serine/threonine protein kinase that plays a critical role in detecting DNA damage and activating repair pathways. When PGDB5-expressing tumor cells were treated with AZD6738 in culture, they exhibited cell death. Conversely, tumor cells without PGDB5 demonstrated resistance to AZD6738 and survived the treatment. AZD6738 showed efficacy against various cultured pediatric cancer cells but did not affect normal embryonic fibroblast cells.

Preclinical Trials and Findings

The researchers further advanced their study by grafting neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells into immunodeficient mice, establishing preclinical in vivo cancer models. Mice were treated orally with AZD6738 or a control treatment, with subsequent monitoring of tumor growth. Results indicated that AZD6738 significantly inhibited tumor growth in medulloblastoma and neuroblastoma but was ineffective against Ewing sarcoma and rhabdoid tumors.

Future Directions and Clinical Trials

Ongoing clinical trials are evaluating the effectiveness of AZD6738 in combination with other chemotherapy agents for various adult cancers, including head and neck squamous cell carcinoma and non-small-cell lung cancer. The findings of this study have prompted some researchers to advocate for testing AZD6738 in pediatric cancer patients, as well as in adults with tumors expressing PGDB5. However, there is a call for caution, as the drug inhibited tumor growth in mice without eradicating the disease. Nevertheless, this discovery paves the way for further exploration and development of therapies targeting DNA damage response signaling for treating refractory solid tumors.

References

(1) Henssen AG, Reed C, Jiang E, et al. Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. *Sci Transl Med.* 2017 Nov 1;9(414). pii: eaam9078. doi: 10.1126/scitranslmed.aam9078. PubMed PMID: 29093183.
(2) Leslie, M. Researchers find fatal flaw in childhood tumors. http://www.sciencemag.org/news/2017/11/researchers-find-fatal-flaw-childhood-tumors. Published November 1, 2017. Accessed: November 10, 2017.
(3) ClinicalTrials.gov. Ascending Doses of AZD6738 in Combination With Chemotherapy and/or Novel Anti Cancer Agents. https://clinicaltrials.gov/ct2/show/NCT02264678. Updated: October 23, 2017. Accessed: November 10, 2017.