Intravenous 5-fluoro-2′-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors

Geraldine O.’Sullivan Coyne, Lihua Wang, Jennifer Zlott, Lamin Juwara, Joseph M. Covey, Jan H. Beumer, Mihaela C. Cristea, Edward M. Newman, Stephen Koehler, Jorge J. Nieva, Agustin A. Garcia, David R. Gandara, Brandon Miller, Sonny Khin, Sarah B. Miller, Seth M. Steinberg, Larry Rubinstein, Ralph E. Parchment, Robert J. Kinders, Richard L. PiekarzShivaani Kummar, Alice P. Chen, James H. Doroshow

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Purpose: Following 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). Methods: Patients 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. Results: Ninety-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. Conclusion: Further 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.

Original languageEnglish (US)
Pages (from-to)979-993
Number of pages15
JournalCancer Chemotherapy and Pharmacology
Volume85
Issue number5
DOIs
StatePublished - May 1 2020

Keywords

  • Cancer epigenetics
  • Circulating tumor cells
  • DNMT1 inhibitors
  • Epigenetic modifying agents
  • p16

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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