2015 — 2019 |
Roper, Jatin |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
The Role of Mtss1 in Hedgehog-Mediated Intestinal Cancer Stem Cell Function
? DESCRIPTION (provided by applicant): According to the cancer stem cell hypothesis, the growth of cancers is driven by long-lived tumor cells that are capable of self-renewal and differentiation. Using the mammalian intestine as a model system, we sought to identify novel molecular pathways regulating Lgr5+ cancer stem cells. Given the central role of Akt in cancer cell fate, differentiation, and proliferation, we interrogated a definitive analysis of the Akt phosphoproteome by the Tsichlis laboratory to identify novel Akt phosphorylation substrates that are enriched in intestinal stem cells and intestinal tumors. Of 22 candidate targets, we selected Mtss1 for further study. We determined that Akt- specific phosphorylation of Mtss1 drives intestinal carcinogenesis and Lgr5+ stem cell clonogenicity in in vitro cell and organoid models by activating Hedgehog signaling. The goal of the current proposal is to study the role of Mtss1 in Hedgehog-mediated tumorigenesis and stem cell function. In the first aim of the proposal, we will examine the role of Mtss1-dependent Hedgehog signaling in intestinal tumorigenesis. In the second aim of the proposal, we will determine the role of Mtss1 in Lgr5+ intestinal cancer stem cell function. Finally, in the third aim of the proposal, determine the role of Mtss1-dependent Hedgehog signaling in Lgr5+ intestinal cancer stem cell function. Our proposal is expected to elucidate Akt and Hedgehog-dependent mechanisms of cancer stem cell function that will provide new therapeutic directions for targeting Lgr5+ tumor stem cells in colorectal, ovarian, gastric, and hepatocellular cancers.
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2021 |
Lee, Chang Lung Roper, Jatin |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Inhibition of Camkk2 Sensitizes Rectal Cancers to Radiation Therapy
Abstract In the United States, colon cancer and rectal cancer are the third most common cancer diagnosed in both men and women. The standard of care for stage II-III rectal cancer is neoadjuvant chemoradiation or short-course radiation followed by total mesorectal excision. However, the response to neoadjuvant radiation varies across patients, with some having minimal response to 10-30% having a pathologic complete response. Pathologic complete response is associated with improved clinical outcomes including resectability, sphincter preservation, local control, and overall survival. Therefore, novel strategies that sensitize rectal cancers to radiation therapy will have great potential to increase pathologic response rates, improve clinical outcomes, and support the emerging total neoadjuvant therapy paradigm and the experimental watch-and-wait approach. The long-term goal of this project is to increase the efficacy of radiation therapy for rectal cancer by targeting calcium/calmodulin-dependent protein kinase kinase 2 (Camkk2). Camkk2 belongs to a family of multifunctional Ser/Thr kinases that participate in the calcium/ calmodulin (CaM) signaling pathway and play a crucial role in controlling energy balance, inflammation and tissue regeneration. Several studies have reported that blocking Camkk2 using genetic approaches or the small molecule inhibitor STO-609 suppresses the growth of breast, prostate and liver cancers in vitro and in vivo. Furthermore, in preliminary studies we found that STO-609 sensitizes mouse colorectal cancer organoids to radiation in vitro. To investigate this question in vivo, we pioneered novel methods to generate solitary, autochthonous tumors in the distal colon that can be monitored with colonoscopy and reproduce the histology of human disease. In preliminary studies, we found that focal pelvic radiation effectively inhibits growth of these tumors. These models represent a major advance over other commonly used colorectal cancer mouse models, which develop many tumors predominantly in the small intestine and are therefore poorly suited to studying radiation therapy of rectal cancer. Based on these findings, we hypothesize that blocking Camkk2 signaling will improve the response to radiation in our novel mouse models of rectal cancer.
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2021 |
Roper, Jatin |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Ultra-Bright Fluorescent Oparticles For Colorectal Adenoma Detection
Abstract Colorectal cancer is the 3rd leading cause of cancer-related mortality. Colorectal cancer screening significantly reduces cancer mortality through the detection of precancerous adenomas and removal with colonoscopy polypectomy. Inspection of the colon upon withdrawal from the cecum during colonoscopy is the most common method of adenoma detection in the United States. However, substantial evidence suggests that there are significant limitations to colonoscopy for adenoma detection due to inadequate visualization of polyps. Therefore, we recently developed ultrabright fluorescent nanoparticles (CA-dots) to highlight adenomas, and thereby, facilitate their detection. In our preliminary study, we showed that these nanoparticles preferentially bind to mouse colon adenomas and human adenoma organoids (i.e., mini-guts grown in three- dimensional environment). In this proposal, we hypothesize that CA-dots conjugated to folate groups will discriminate between adenoma and normal colon derived from colonoscopy subjects with high sensitivity and specificity. In Specific Aim 1, we will synthesize CA-dots for targeting of human adenomas. The goal of this aim is to prepare ultrabright fluorescent nanoparticles composed of cellulose acetate that demonstrate the highest accuracy in identification of colorectal adenomas. In Specific Aim 2, we will determine the efficacy of targeting fluorescent nanoparticles (CA-dots) to visually distinguish adenoma of various types from normal colon tissue. Here, we will study the efficacy of our CA-dot functionalized with folic acid to distinguish adenoma tissue from normal colon tissue biopsy specimens derived from a cohort of subjects who are referred to Duke University Hospital for removal of large (> 2 cm) adenomas. The goal of this proposal is to demonstrate efficacy of our novel fluorescent nanoparticles, CA-dots, to discriminate colon adenoma from normal colon ex vivo. Results from this study will provide preliminary data for R01-level applications to examine the application of this technology for the detection of precancerous adenomas during screening colonoscopy, which is our overarching goal.
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