Targeting the ALDH+ Tumorigenic Population in Colorectal Cancer
Abstract
Fiscal Year 2014 Prostate Cancer Research Program Topic Area: This proposed project directly relates to the topic area of colorectal cancer (CRC) through the advancement of novel combinations that target the tumorigenic population for the treatment of military personnel and their families with CRC. Scientific Objective and Rationale for the Proposed Project: The WNT and Notch pathways are very important in regulating the stem cell population of cells in the colon. Alterations in these pathways have a significant impact in the development of CRC. In addition, WNT and Notch activation following the treatment with chemotherapy are associated with resistance to these therapies. The objective of this proposed project are: (1) to have a better understanding of the WNT and Notch pathways in regulating the renewal of cancer cells as well as its role in mediating resistance to chemotherapy and (2) to determine whether targeting the WNT and Notch pathways in combination and/or with chemotherapy will enhance antitumor activity. Ultimate Applicability of the Research: Approximately 25% (35,705 patients - 2013 estimates) of CRC patients will be diagnosed with advanced metastatic disease. Of the remainder, ~75% of CRC patients, ~50% (53,558 patients - 2013 estimates) of patients will develop recurrence that is incurable with a median of 2-3 years. Since the dysregulation of the WNT (>90% of patients with CRC) and Notch pathways (>50% of patients) occurs in a significant portion of this patient population, inhibition of these pathways in combination may significantly improve survival. Given that the activation of the WNT and/or Notch pathways appears to be important in facilitating resistance to chemotherapy (standard of care for CRC patients), targeting these pathways with novel single agents + chemotherapy and in combination (WNT+Notch+chemotherapy) may also yield improved outcomes in these patients. Importantly, both WNT and Notch pathway inhibitors are currently being evaluated in the clinic, which allows us to translate these findings of this work into the clinic. We plan to pursue an investigator-initiated (Dr. Messersmith - my post-doc mentor and close collaborator) Phase II clinical trial with WNT and Notch inhibitors as a single agents or in combination with irinotecan in patients with metastatic CRC (including the Veterans Affairs Medical Center [VAMC]) immediately following the completion of this proposed study. The proposed studies will greatly enhance our understanding of the interaction of the WNT and Notch pathways in tumorigenic growth and in its role in enhancing resistance to chemotherapy. This study will advance the field of treatment by being able to target the major pathways that are dysregulated in patients with CRC. How the Proposed Research Will Benefit Active Duty Service Members, Their Families, and Other Military Beneficiaries: After completion of this project, we plan to open a clinical trial with the Notch and WNT inhibitors as a single agent or in combination including chemotherapy. This will include the VAMC where Veterans if eligible can participate in this study. Eventually, military personnel and their families may receive this therapy if these agents are approved by the Food and Drug Administration for the treatment of CRC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510173
Entities
People
- John Arcaroli
Organizations
- United States Army
- University of Colorado Denver