PLX038: A Long-Acting Topoisomerase I Inhibitor With Robust Antitumor Activity in ATM-Deficient Tumors and Potent...

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• ATM gene alterations are frequent in various cancers.
• ATM-deficient tumors exhibit heightened sensitivity to DNA-damaging agents.
• Synthetic lethal strategies combining DNA-damaging agents and repair inhibitors are promising but face toxicity challenges.

Purpose of the Study:

• To investigate the efficacy of PLX038, a novel topoisomerase I inhibitor conjugate, in ATM-deficient and BRCA1-deficient cancers.
• To evaluate PLX038 as monotherapy and in combination with PARP inhibition.
• To explore new therapeutic paradigms for ATM-loss cancers.

Main Methods:

• Utilized ATM wild-type and null isogenic xenografts.
• Tested a BRCA1-deficient xenograft model.
• Administered PLX038 as monotherapy and in combination with PARP inhibitors.
• Reported a case study of a patient with ATM-mutated breast cancer.

Main Results:

• PLX038 monotherapy and combination therapy potently inhibited tumor growth in both BRCA1- and ATM-deficient models.
• A patient with ATM-mutated breast cancer achieved a complete response lasting 12 months with PLX038 and rucaparib.
• Demonstrated the potential of PLX038 in combination with DNA damage response inhibitors.

Conclusions:

• PLX038, alone or with PARP inhibitors, demonstrates significant anti-tumor activity in ATM-deficient and BRCA1-deficient cancers.
• This approach represents a novel therapeutic strategy for cancers with ATM loss.
• Further investigation into PLX038 and DNA damage response inhibitors is warranted for clinical translation.