2010 — 2014 |
Samant, Rajeev S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Nmi in Retarding Breast Tumor Growth. @ University of South Alabama
DESCRIPTION (provided by applicant): Research in our laboratory focuses on understanding the role of N-Myc interactor (Nmi) in cancer biology [1]. Our interest in this molecule was triggered when we saw that its expression was diminished in aggressive breast cancer cell lines. Interestingly though, Nmi expression could be induced in these cells using interferon-? (IFN-?) [1]. We found that the induced mRNA had a wild type sequence, implying that the induced Nmi protein was capable of its normal biological activities. To test its functional role, we constitutively expressed Nmi in the human breast cancer cell line, MDA-MB- 231. Functional studies of the expressors showed that Nmi reduced the ability of tumor cells to invade and grow under anchorage independent conditions. Xenograft studies in nude mice showed that Nmi expressors had reduced tumor growth in vivo [1]. Further analysis of these expressors revealed that Dickkopf-1 (Dkk1), a soluble inhibitor of the Wnt/?- catenin signaling pathway, was significantly upregulated in the Nmi expressing clones concurrent with reduced levels of the critical transcription co-factor of Wnt pathway, ?-catenin. Dkk1 has been reported to suppress primary tumor growth rates in several studies involving breast cancer [2, 3] and is a factor implicated in the anti-tumor effects elicited by IFN-? [4]. Wnt/?-catenin signaling is important in development as well as cell proliferation. While previously shown to be a critical player in colon cancer progression, the role of Wnt/?-catenin signaling in breast cancer is not clearly defined [5]. The overall objective of this proposed work is to understand the regulation of Wnt/?-catenin signaling by Nmi and to determine the role of this pathway in suppression of breast tumor growth. HYPOTHESIS Inhibition of the Wnt/?-catenin signaling pathway by upregulation of Dkk1 is critical to the role of Nmi in reducing tumor growth. Aim 1: To test the hypothesis that knockdown of Nmi expression will activate the Wnt/?-catenin signaling. Aim 2: To determine the mechanism of regulation of Dkk1 and ?-catenin by Nmi. Aim 3: To evaluate the role of Dkk1 in mediating the retardation of tumor growth by Nmi. Aim 4: To determine correlation between loss of Nmi expression and activated Wnt/?-catenin signaling in patient derived breast cancer specimens. PUBLIC HEALTH RELEVANCE: Our preliminary data demonstrates a functional role of Nmi in retarding breast tumor growth. This proposal takes the research to a next essential step in establishing the translational potential of Nmi and the downstream events that it regulates. The focus of this research is the Wnt/?-catenin pathway. Nmi up-regulates Dkk1, a secreted inhibitor of Wnt pathway, leading us to propose that Nmi down regulates Wnt/?-catenin signaling, resulting in reduced malignant activity of breast cancer.
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1 |
2016 — 2020 |
Samant, Rajeev S |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dietary Intervention of Non-Classical Wnt Signaling @ University of Alabama At Birmingham
? DESCRIPTION (provided by applicant): The invasive and metastatic nature of breast cancer poses a formidable challenge due to the associated therapeutic resistance, disease relapse and mortality. The behavior of cancer cells is dictated by their interaction with their surrounding tissue. Osteopontin (OPN) is a critical component of breast stroma. OPN is overexpressed in over 70% cases of malignant breast neoplasms and its overexpression is indicative of poor prognosis. OPN potentiates malignant properties of cells, specifically by promoting their ability to grow, invade, and metastasize. Wnt signaling is dysregulated in breast cancer. We showed that mis-regulation of Wnt homeostasis results in EMT activation and malignant progression. We also demonstrated that DNAJB6, a member of HSP40 family of chaperones, interferes with Wnt/?-catenin signaling and in fact, acts as a gatekeeper of EMT resulting in reduced metastasis. In invasive progression of breast cancer, DNAJB6 protein expression is compromised. Loss of DNAJB6 expression is one of the key factors that promote secretion of OPN by the tumor cells. The central hypothesis of this proposal is that OPN activates Wnt-ligand independent, non-classical ?- catenin signaling, leading to malignant progression of breast cancer. This non-classical activation of ?- catenin activity has profound implications with respect to tumor progression, multi-drug resistance and importantly to Wnt inhibitors being tested in the clinic. Based on compelling observations regarding its ability to counteract Wnt signaling, and restore DNAJB6 expression, we propose to test the dietary flavonoid, fisetin for reversing or preventing EMT and resistance to drug treatment. Fisetin is abundantly present in mangos, strawberries etc. and thus are an affordable means of dietary supplementation. Our objectives are (i) To characterize the mechanisms and effects of non-classical activation of ?-catenin signaling and (ii) To determine if fisetin serves as an effective functional food to revere EMT and prevent metastasis. We will also test fisetin's impact on improving sensitivity of breast cancer cells to cytotoxic chemotherapy. The outcome will allow use of fisetin as a dietary intervention to block non-classical ?-catenin signaling due to OPN in the tumor microenvironment. The work will also test prevention strategies to intervene in metastatic dissemination of breast cancer. Impact: Considering the emphasis of ongoing clinical trials on inhibition of Wnt signaling, the proposed work will have immediate impact on the course of ongoing clinical trials. This research has the potential to complement costly and debilitating chemotherapy regimens.
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0.982 |
2020 |
Samant, Rajeev S |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Project 1: @ University of Alabama At Birmingham
7. PROJECT SUMMARY African Americans (AAs) are more likely to develop and die from cancer than any racial and ethnic group in the United States (U.S.). Over the past two decades, there has been an increased focus on participation of AAs in cancer clinical trials (CCTs) to address this disproportionate burden of cancer; however AAs continue to be underrepresented in CCTs. The dearth of AAs participating in CCTs diminishes the generalizability of results of trials. If AAs remain underrepresented in CCTs, the implications include slower progress in elucidating the underlying causes of long-standing health disparities in cancer outcomes. There is an extensive body of science detailing trial participation barriers among AAs, including limited access to specialty care centers where trials are conducted, competing work obligations, and fear and mistrust of clinical research. Despite these barriers, AAs are, inherently, no less willing to participate in CCTs or other types of research studies than other racial or ethnic groups. The absence of differences in willingness to participate suggests that persistent disparities in accrual may, in fact, be due to AAs being offered fewer opportunities than whites to participate in CCTs. Although many interventions have focused on approaches to increase the willingness of AAs to participate, perhaps efforts should be focused on increasing the opportunities among AAs to participate in CCTs. We propose to adapt the IMPaCT patient navigation model and pilot a clinical trials navigator program, IMPaCT 2.0, at Morehouse Healthcare (MH) and Grady Hospital (Grady), one of the largest safety-net hospitals in the nation. We propose to enhance the patient navigation model with a mobile tablet-based clinical trial tracking system (CTTS) (using i2b2 software) to facilitate increased engagement among AA patients regarding CCT participation opportunities and to address deficits in the research infrastructure at these two institutions. Utilizing a qualitative approach, we will identify those barriers and facilitators to AA recruitment at MH/Grady (Specific Aim 1) and incorporate those findings into an adapted clinical trials navigation (CTN) model with an integrated mobile tablet CTTS (Specific Aim 2)., We will implement IMPaCT 2.0 at MH/Grady breast and prostate cancer clinics and evaluate, in a one-group, pre-/post-test design, the feasibility and acceptability (Specific Aim 3).
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0.982 |