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Ref Type Journal Article
PMID (35999657)
Authors Thomas A, Fontaine SD, Diolaiti ME, Desai P, Kumar R, Takahashi N, Sciuto L, Nichols S, Ashworth A, Feng FY, Ashley GW, Nguyen M, Pommier Y, Santi DV
Title PLX038: A Long-Acting Topoisomerase I Inhibitor With Robust Antitumor Activity in ATM-Deficient Tumors and Potent Synergy With PARP Inhibitors.
Journal Molecular cancer therapeutics
Vol 21
Issue 11
Date 2022 Nov 03
URL
Abstract Text Alterations in the ATM gene are among the most common somatic and hereditary cancer mutations, and ATM-deficient tumors are hypersensitive to DNA-damaging agents. A synthetic lethal combination of DNA-damaging agents and DNA repair inhibitors could have widespread utility in ATM-deficient cancers. However, overlapping normal tissue toxicities from these drug classes have precluded their clinical translation. We investigated PLX038, a releasable polyethylene glycol-conjugate of the topoisomerase I inhibitor SN-38, in ATM wild-type and null isogenic xenografts and in a BRCA1-deficient xenograft. PLX038 monotherapy and combination with PARP inhibition potently inhibited the growth of both BRCA1- and ATM-deficient tumors. A patient with an ATM-mutated breast cancer treated with PLX038 and the PARP inhibitor rucaparib achieved rapid, symptomatic, and radiographic complete response lasting 12 months. Single-agent PLX038 or PLX038 in combination with DNA damage response inhibitors are novel therapeutic paradigms for patients with ATM-loss cancers.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
ATM Q1970* breast ductal carcinoma predicted - sensitive PLX038 + Rucaparib Case Reports/Case Series Actionable In a clinical trial, PLX038 and Rubraca (rucaparib) combination treatment resulted in a complete response within the first treatment cycle, followed by PLX038 monotherapy, which resulted in maintenance of tumor suppression for a total of 12 months in a patient with metastatic breast ductal carcinoma harboring germline ATM Q1970* (PMID: 35999657; NCT04209595). 35999657
ATM del prostate cancer sensitive PLX038 + Talazoparib Preclinical - Cell line xenograft Actionable In a preclinical study, PLX038 and Talzenna (talazoparib) combination treatment resulted in synergistic inhibition of tumor growth and increased event-free survival in a cell line xenograft model of prostate cancer harboring ATM deletion (PMID: 35999657). 35999657
ATM del prostate cancer sensitive PLX038 Preclinical - Cell line xenograft Actionable In a preclinical study, PLX038 resulted in inhibition of tumor growth and increased event-free survival in a cell line xenograft model of prostate cancer harboring ATM deletion (PMID: 35999657). 35999657