Women with advanced triple negative breast cancer (negative for estrogen and progesterone receptor expression and HER-2 gene/neu amplification) have a very poor prognosis necessitating novel therapeutic strategies to improve survival. Triple negative breast cancer typically falls into the molecular classification of basal-like subtype which has a higher rate of TP53 and/or PTEN mutations. In this investigation, based on a clinical protocol approved by the National Cancer Institute's Cancer Therapy Evaluation Program, we will treat patients with advanced triple negative breast cancer with the combination of irinotecan and UCN-01, a broad spectrum serine-threonine protein kinase inhibitor that targets both 3-phosphoinositide-dependent protein kinase-1(PDK1) and checkpoint kinase, CHK1. The primary aim is to evaluate the efficacy and safety of this combination. The secondary aims are to develop a portfolio of pharmacodynamic and predictive biomarkers that may prove useful for the development of CHK1 and PDK1 inhibitors for the treatment of triple negative breast cancer. The primary aims of this proposal are: 1.To determine the anti-tumor activity (overall response rate, clinical benefit rate, and time to disease progression) of UCN-01 in combination with irinotecan in triple negative advanced breast cancer that has progressed despite prior treatment with an anthracycline and a taxane. 2. To describe the toxicities associated with irinotecan in combination with UCN-01 in triple negative advanced breast cancer. The secondary aims of this proposal are: 1. To analyze the frequency of TP53, PTEN and PIK3CA mutations in triple negative advanced breast cancer and conduct preliminary correlations with treatment response to irinotecan in combination with UCN-01. 2. To better define the population of triple negative breast cancers enrolled into the trial with qRT PCR and immunohistochemical biomarkers for the basal sub-type as well as other breast cancer subtypes. 3. To develop methodologies for pharmacodynamic monitoring of the effect of UCN01 on tumor CHK1 and PDK1 by analyzing the levels of CDC25A, and the phosphorylation status of CDK1(Tyr15), PDK1(Ser241) and AKT1 (Thr308) on basal-type cell lines (as controls) as well as sequential tumor biopsy specimens in patients treated on this study. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA128369-01
Application #
7275903
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Xie, Heng
Project Start
2007-09-24
Project End
2009-08-31
Budget Start
2007-09-24
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$278,385
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Ma, Cynthia X; Ellis, Matthew J C; Petroni, Gina R et al. (2013) A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer. Breast Cancer Res Treat 137:483-92