A phase II trial to evaluate clinical efficacy, pharmacodynamics and exploratory analysis of pemetrexed in relation to MLL4 and UTX alteration status in patients with relapsed/refractory metastatic urothelial carcinoma and other solid tumors
Abstract
TPS4621
Background:
MLL4 (encoded by KMT2D) and UTX (encoded by KDM6A) are protein components of the epigenetic chromatin modifier complex COMPASS. MLL4 alterations are found in ~10% of all cancers including ~29% of bladder cancer (BLCA). UTX alterations are found in up to ~5% of all cancers including ~29% of BLCA. These alterations have not been previously therapeutically targeted as a precision oncology strategy in humans despite their frequency. We recently published the results of a CRISPR/Cas9 knockout screen in cells lacking MLL4/UTX-COMPASS function, which revealed synthetic lethality upon loss of genes that encode enzymes involved in de novo nucleotide synthesis (dnNS) [Zhao et al. J Clin Invest. 2023; Zhao et al. PNAS. 2023]. We also reported that MLL4 truncation mutations confer an inhibitor-targetable dependence on dnNS in colorectal cancer (CRC) and BLCA. We demonstrated sensitivity to lometrexol, which targets the enzyme GART (glycinamide ribonucleotide formyltransferase), in animal models of CRC and BLCA with MLL4 truncation. Our preclinical results clearly indicated the potential for dnNS inhibition as a targeted therapy for patients stratified by MLL4 or UTX status. Pemetrexed was identified as a more clinically relevant purine synthesis inhibitor for further development due to its well-established safety profile and prior use in BLCA.
Methods:
We have initiated an investigator-initiated, open-label phase II basket clinical trial at Northwestern University…
How strong is the evidence?
Evidence Hub reads this as a secondary / pooled analysis, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 64 participants or records.
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