Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	21	11	2022 Nov 03	1722-1728	Mol Cancer Ther

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 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
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