Skip NavigationSkip to Content
Return Return to Search Results

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

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

  2. Author Address

    Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA., Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Clinical Monitoring Research Program, Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA., Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA., City of Hope Medical Group, South Pasadena, CA, USA., University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA., Louisiana State University, New Orleans, LA, 70112, USA., University of California Davis Cancer Center, Sacramento, CA, USA., Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg. 31 Room 3A-44, Bethesda, MD, 20892, USA. doroshoj@mail.nih.gov., Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. doroshoj@mail.nih.gov.,
    1. Year: 2020
    2. Date: Apr 20
    3. Epub Date: 2020 04 20
  2. Journal: Cancer chemotherapy and pharmacology
  4. Type of Article: Article
  1. 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.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1007/s00280-020-04073-5
  3. PMID: 32314030
  4. PII : 10.1007/s00280-020-04073-5

Library Notes

  1. Fiscal Year: FY2019-2020
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel