Status: Filled – Intern: Kevin Luque-Sanchez
Intern: Kevin Luque-Sanchez
Faculty Name: renata-jaskula-sztul
UAB Department: Surgery
UAB School: UAB School of Medicine
Campus Address: 310H Wallace Tumor Institute; 1824 6th Av South
Telephone Number: (205) 975-3507
Email: sztul@uab.edu or Click to Send E-Mail
For how many summers have you served as a preceptor: 3 or more
CCC Research Area: Cancer Biology
Number of hours per week that the preceptor will personally supervise or work with the intern: 20
Other faculty, staff, or graduate students who may help to supervise the intern:
1. Jason Whitt, PhD
2. Rachael Guenter, graduate student
Title of Project: 41RJ – Detecting the alterations in SSTR2 expression with HDAC inhibitors treatment for neuroendocrine cancer therapy
Project Description:
Neuroendocrine (NE) cancers such as carcinoids, pancreatic islet cell tumors, and medullary thyroid cancer (MTC) frequently metastasize to the liver. Despite various complex management strategies for NE liver metastases, surgery is the only treatment that offers potential for cure. There is a critical need to de¬ve¬lop new therapeutic options to reduce NE cancer progression and excessive hormone secretion.
More recently, NET imaging using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2) is becoming more standard as many NETs overexpress SSTR2. Just as importantly, NET patients with low SSTR2 expression are not eligible for newly developed promising treatments which target SSTR2. We have found that an HDAC inhibitors can upregulate the expression of SSTR2 in NET cell lines. In this study we will use a non-cytotoxic dose of TDP-A, FK228 and entinostat to induce SSTR2 expression. Our hypothesis is that the HDAC inhibitors can upregulate NET SSTR2 expression in vitro and in vivo to improve SSTR2-specific targeting for tumor imaging and potential treatments.
Specific Aim: To test the ability of the HDAC inhibitors to upregulate NET SSTR2 expression in vitro and in vivo for im¬proved diagnostics and therapeutic targeting.
Our in vitro preliminary studies have shown an upregulation of SSTR2 at the protein level following treatment by HDACi’s. We have measured the basal protein expression level of SSTR2 in human different NET cell lines. Interestingly, the pulmonary carcinoid cell line H727 has the lowest basal expression of SSTR2 among all NET cells. In this proposed study, we will continue experiments using NET cell lines H727, UMC11, BON, QGP, TT and MZ. To further investigate the effects of HDACi on SSTR2, we will test SSTR2 gene expression through RT-PCR and Western blot before and after treatment with this HDACi. We have begun evaluating the effect of TDP-A on SSTR2-based imaging by performing both an image stream and flow cytometry analysis on NE carcinoid cells pre-treated with TDP-A and followed by detecting the specific binding of octreotide fluorescently labeled with Cy5 (OCT-Cy5). OCT is a somatostatin analog with high targeting affinity to SSTR2 that we labeled with Cy5, a fluorophore for visualization. After treating NET cells with TDP-A, we observed improved binding of this analog. The flow cytometry analysis con¬firmed a 2-fold increase in the uptake of OCT-Cy5 after the TDP-A pre-treatment. This SSTR2 upregulation technique is extremely novel and has the potential to allow for a new method of imaging and potential targeted treatments for NET patients.
More information can be found in the recently published papers:
1. Guenter R, Aweda T, Carmona Matos DM, Whitt J, Chang AW, Cheng E, Liu MX, Chen H, Lapi SE, Jaskula-Sztul R. Pulmonary carcinoid surface receptor modulation using histone deacetylase inhibitors. Cancers, 2019 Jun 3; 11(6). PMCID:PMC6627607
2. Guenter R, Aweda T, Whitt J, Chang A, Liu XM, Chen H, Lapi SE, Jaskula-Sztul R. Overexpression of somatostatin receptor type 2 (SSTR2) in neuroendocrine tumors for improved [68Ga]DOTATATE imaging and treatment. Surgery, 2020 Jan;167(1):189-196. PMID:31629542
Project Status: Already up and running
Location of Project: Birmingham, AL (UAB)
Proposed Start Date: June 1, 2020
Proposed End Date: August 14, 2020
Expected work schedule for intern: Not very flexible, intern MUST be at work on certain days of the week and at certain times of the day (as may be necessary to interview patients, attend lab meetings, process samples, etc.) and should contribute full-time effort.
Category of Project: Laboratory Research
Cancer topic: Lung and Bronchus, Pancreas, Thyroid
Does this project involve human subjects: No
Does this project involve animal subjects: Yes
Duty:
1.
NET cell culturing and treatment
2.
performing RT-PCR, Western blots, flow cytometry
3.
analyze data
Preceptor will provide intern with access to the following:
Office or desk space, Computer and printer, Laboratory work bench space, Supplies needed to complete project, Equipment needed to complete project
Likelihood that intern will be included as an author on one or more publications
related to this summer research project: Very likely
Areas in which the ideal candidates will have experience:
Biochemistry, Cell Biology, Laboratory Skills, basic knowledge, Pharmacology
