Although activation of the Ras/Raf/MEK/ERK pathway is involved in cell growth, inhibition of apoptosis, induction in stem-like phenotype, and drug resistance, little is known about its dynamic control and plasticity. Recent studies have suggested that the functional crosstalk between APC/Wnt/-catenin and RAS-ERK pathways plays an important role in colorectal cancer (CRC) progression and metastasis. Our initial data suggest that the MEK/ERK pathway and subsequently Wnt/-catenin signaling are activated by STRAP (Serine Threonine Kinase Receptor Associated Protein) that we cloned several years ago. We have shown that STRAP is upregulated in more than 70% of CRCs and induces cell proliferation, tumorigenicity, self- renewal of cancer stem-like cells (CSC), and drug resistance. We have observed that conditional knockout of Strap in mice decreases the number and size of intestinal tumors induced by genetically inactivated APC (Apc Min). We showed that STRAP induces CRC metastasis in vivo in a spontaneous metastasis model. In CRC patients, upregulation of STRAP is associated with worse survival following adjuvant therapy. In contrast, patients carrying tumors with normal or low STRAP expression benefited from the treatment, suggesting its potential role in chemoresistance. Interestingly, we showed that reduced expression of STRAP enhances drug (5-FU and Oxaliplatin)-induced apoptosis and sensitizes cells to chemotherapy in vitro and in vivo. Therefore, these in vitro and in vivo studies provide the proof-of-concept that abrogating STRAP signaling in CRC will decrease tumorigenicity and metastasis and will sensitize CRC tumors to chemotherapy. We already have developed a nanocarrier PMBOx-PMPOy-PMEOz to achieve in vivo codelivery of STRAP siRNA and 5-FU-Oxp- OA (oleic acid motif). We have observed that nanoparticle-mediated delivery of STRAP siRNA decreases cell proliferation, migration and invasion. Based on the preliminary information, we have formulated the hypothesis: Therapeutic targeting of pro-oncogenic functions of STRAP by siRNA-based nanoformulation will be effective in treating CRC patients as well as sensitizing CRC patients with 5-FU and/or Oxaliplatin based chemotherapy. The following Specific Aims are proposed:
Aim 1 : Determine how STRAP activates MEK/ERK pathway and subsequently Wnt/-catenin signaling in colorectal cancer.
Aim 2 : Characterize tumor-promoting functions of STRAP in vivo and determine its role in the development and progression of spontaneous intestinal tumors.
Aim 3 : Develop a novel therapy that is based on siRNA-mediated silencing of STRAP using nanoparticles (NPs) alone and in combination with codelivery of 5-FU and Oxaliplatin. Impact: As 1) STRAP inhibits the tumor suppression function of TGF-; 2) it promotes CSC self- renewal and drug resistance; 3) upregulation of STRAP exerts tumor promoting effects including invasion and metastasis; 4) its upregulation in CRC patients contributes to worse survival with chemotherapy; 5) it induces tumorigenicity through inactivated APC signaling, activated Wnt/-catenin, and MEK/ERK pathways; and 6) its knockout in cells and mice have no effect on normal physiological functions; STRAP is a promising and unique therapeutic target. Therefore, this first attempt of targeting STRAP by improved siRNA-mediated silencing strategy using a multifunctional nanomicellar carrier alone and in combination with codelivery of 5-FU and Oxaliplatin will provide strong translational potential to develop pre-therapeutic leads for colon cancer. Smoking has been shown to have causal effects on colon and rectal cancers in significant percentage of veteran men and women especially over 50 years of age. Therefore, this innovative and preclinical biomedical research has the potential for significant advances in healthcare for veterans. This project will include two priority research areas of specific interest to BLR&D, 1) risky behavior related to smoking and 2) women veteran's health (RFA# BX-19-001).
As with the overall national population, colorectal cancer remains the second leading cause of cancer death in the US veteran population. During the last 40 years, the proportion of colorectal cancer has increased by about 15% in the veteran population and thus constitutes a significant health risk for all veterans and their family members including women especially over 50 years of age. The aberrant regulation of tumor suppressor genes and oncogenes plays a pivotal role in the transformation of normal epithelium into carcinoma in situ and metastatic cancer. STRAP, a cellular protein, is upregulated in colon cancer, promotes cell proliferation, tumorigenicity, metastasis, cancer stem-like cell (CSC) self-renewal, and drug resistance, thus contributing to worse survival of patients with chemotherapy. This study will discover novel and less toxic nanoparticles targeting STRAP, which will be used to codeliver 5-FU and Oxaliplatin. The proposed research is very crucial for the development of successful therapeutic strategies for colon cancer.
