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|Ref Type||Journal Article|
|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|
|Date||2022 Nov 03|
|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.|
|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|