FL3 anti-cancer mechanism in the intestine.

Information

  • Research Project
  • 9679711
  • ApplicationId
    9679711
  • Core Project Number
    F32CA228227
  • Full Project Number
    1F32CA228227-01A1
  • Serial Number
    228227
  • FOA Number
    PA-18-670
  • Sub Project Id
  • Project Start Date
    7/17/2019 - 4 years ago
  • Project End Date
    -
  • Program Officer Name
    JAKOWLEW, SONIA B
  • Budget Start Date
    7/17/2019 - 4 years ago
  • Budget End Date
    -
  • Fiscal Year
    2019
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    1/17/2019 - 5 years ago

FL3 anti-cancer mechanism in the intestine.

Project Summary Patients with chronic inflammatory bowel diseases (IBD) affecting the colon have increased risk for colorectal cancer (CRC), accounting for nearly 10-15% of deaths in IBD patients. CRC developed as a consequence of chronic colonic inflammation is referred to as colitis-associated cancer (CAC). Due to the well-established association of chronic inflammation with CRC development, the use of anti-inflammatory agents to impede carcinogenesis is considered an effective strategy for CRC chemoprevention. In search of a novel anti- inflammatory agent to prevent CAC, I utilized FL3, a novel compound synthetically produced from natural compounds named flavaglines found in medicinal Aglaia plants. My preliminary data demonstrate that FL3 reduces tumor development in a mouse model of CAC. FL3 treatment of 3D cultures of tumors (tumoroids) from these mice increased tumor cell death and induced genes that inhibit the Wnt/?-catenin pathway, a pathway that is commonly activated in intestinal tumors. Based on these data, the hypothesis for the proposed study is that FL3 exhibits anti-cancer properties in the intestine via inhibition of Wnt/?-catenin signaling. Specific aims are: 1) determine whether FL3 alters oncogenic properties via inhibition of Wnt/?-catenin signaling in CRC cell lines and tumoroids carrying activating mutations in the Wnt/?-catenin pathway, 2) determine whether FL3 alters oncogenic properties via inhibition of Wnt/?-catenin signaling in vivo in the APCMin/+ mouse model. Recently, NIH expressed interest in early phase clinical trials of natural products, which have a specific mechanism of action as shown in preclinical studies. My approach will elucidate FL3?s ability to combat tumorigenesis in preclinical models via the specific mechanism of enhanced ?-catenin inactivation and degradation through induction of Axin1. Results from these studies are intended to provide information to accelerate the translation of preclinical findings about FL3 into early stage clinical testing, which is of intense interest to NIH.

IC Name
NATIONAL CANCER INSTITUTE
  • Activity
    F32
  • Administering IC
    CA
  • Application Type
    1
  • Direct Cost Amount
    61610
  • Indirect Cost Amount
  • Total Cost
    61610
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    398
  • Ed Inst. Type
  • Funding ICs
    NCI:61610\
  • Funding Mechanism
    TRAINING, INDIVIDUAL
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    BAYLOR RESEARCH INSTITUTE
  • Organization Department
  • Organization DUNS
    145745022
  • Organization City
    DALLAS
  • Organization State
    TX
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    75201
  • Organization District
    UNITED STATES