Abstract
PurposeFollowing promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs).MethodsPatients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis.ResultsNinety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal—though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response.ConclusionFurther study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.
Highlights
Many malignancies are characterized by DNA methylationmediated silencing of tumor suppressor gene expression
Based on survival and response metrics from prior studies, FdCyd combined with THU was designated as worthy of further testing in nonsmall cell lung cancer (NSCLC), urothelial, or head and neck (H&N) cancer if ≥ 6 objective responses (≥ 13%), or ≥ 18 instances of 4-month progression-free survival (PFS) (≥ 40%), were observed among 45 enrolled patients; for the breast stratum, the regimen was considered worthy of further testing if ≥ 5 objective responses (≥ 14%), or ≥ 15 instances of 6-month PFS (≥ 43%), were observed among 35 enrolled patients
Our efficacy results suggest that further testing of the FdCyd + THU combination is potentially warranted only in patients with urothelial transitional cell carcinoma, but not in NSCLC, H&N cancer, or breast cancer
Summary
Many malignancies are characterized by DNA methylationmediated silencing of tumor suppressor gene expression. DNA methyltransferase (DNMT) enzymes catalyze the addition of a methyl group at the 5 position of cytosine residues found within CpG dinucleotide-rich islands throughout the genome, and frequent overexpression of DNMTs in tumor cells yields increased methylation of CpG islands within promoters and other regulatory regions [1]. This hypermethylation recruits proteins involved in heterochromatin formation, leading to transcriptional repression. CDKN2A is one of the most frequently methylated genes across common cancer types and is often differentially silenced in primary tumors and tumor cell lines relative to non-malignant cells [2]. P16 expression represents a promising approach for monitoring the PD effects of DNMT inhibition
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