In Full Stride – Catching up with Previously Featured Projects
Catching up with NSU investigators and research projects featured in previous newsletters.
Following up with Appu Rathinavelu PhD, executive director of the Rumbaugh-Goodwin Institute for Cancer Research, and professor at the Silverman College of Pharmacy, along with his team about discovering and patenting (description below) a compound – code-named F16 – which is showing promising results in pre-clinical testing for the treatment of Glioblastoma (abstract/citation below). The Institute, in consultation with the university’s Office of Research and Technology Transfer, have engaged a well-known Clinical Research Organization to externally validate these findings and prepare for Investigational New Drug (IND) filing with FDA.
Faculty spotlight link below,
Discovery of a Compound (F16) with a Promise for Treatment of Glioblastoma
Technology – Small Molecule F-16
The technology is a therapeutic method that implements the use of a small molecule, F16, which binds to and inhibits the Vascular Endothelial Growth Factor-2 (VEGF) receptor and prohibits angiogenesis. Therefore, it slows down or prevents formation of vasculature essential for the tumor’s survival and starves the cancer to death. Passing through the blood-brain-barrier (BBB) is a major obstacle for therapeutic molecules used to treat brain cancers such as GBM. Owing to the relatively small molecular size of F16, it can traverse the BBB as demonstrated by its efficacy against in vivo GBM mouse models. In preliminary in vitro and in vivo experiments, F16 was demonstrated to have both anti-angiogenic and pro-apoptotic properties, making it an ideal candidate for treating a brain cancer such as GBM whose survival and growth is reliant upon increased vasculature development. Efficacy of F16 in treating brain cancer and secondary toxic effects were tested and compared with currently used chemotherapy drugs temozolomide and paclitaxel. In these preclinical studies, F16 demonstrated better or equivalent efficacy and less secondary toxicity compared with both chemotherapy drugs. Thus, F16 provides a new treatment modality for brain cancers such as GBM.
https://www.nova.edu/ott/forms/Glioblastoma-therapy_-Dr.-Rathinavelu.pdf
Evaluation of anti-angiogenic agent F16 for targeting glioblastoma xenograft tumors
Glioblastoma Multiforme (GBM) is one of the most aggressive and lethal types of all cancers, with an average 5-year survival rate of 5%. Since GBM tumors are highly vascularized tumors, and their growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors were considered as one of the promising approaches. In this context, intensive preclinical evaluation of a novel small molecule named F16 has exhibited potent anti-angiogenic and anti-tumor activities by selectively antagonizing Vascular Endothelial Growth Factor Receptor (VEGFR). Also, recent pharmacokinetic evaluation of F16 with tissue distribution analysis has shown that this molecule is transported across the blood-brain barrier (BBB) and accumulates in the brain regions with no signs of neurotoxicity. Therefore, further studies were conducted to determine the efficacy of F16 in delaying glioblastoma progression via inhibiting tumor angiogenesis. Our in vitro studies have clearly demonstrated the ability of F16 to inhibit migration and invasion of U87MG cells and also confirmed a potent cytotoxic effect against these cells in comparison to Temozolomide (TMZ). Our in vivo studies with the subcutaneously implanted (s.c.) xenograft tumor model and in vitro studies have clearly demonstrated the ability of F16 to delay tumor growth and inhibit migration and invasion.
Algahtani M, Natarajan U, Alhazzani K, Alaseem A, Rathinavelu A. Evaluation of anti-angiogenic agent F16 for targeting glioblastoma xenograft tumors. Cancer Genetics. 2022;264-265:71-89. doi:10.1016/j.cancergen.2022.04.001
Following up with Dmitriy Minond PhD, Associate Professor in the Barry and Judy Silverman College of Pharmacy and Rumbaugh Goodwin Institute for Cancer Research, about his Florida Department of Health grant that we featured in our 2023 Research Report, links below:
https://www.nova.edu/publications/dor-report/17/
At the 2023 American Association for Cancer Research (AACR) Annual Meeting, Maab Khalid Sultan, Ph.D Candidate in Molecular medicine and pharmacogenomics, from Dr. Minond’s team presented results from work related to their Florida Department of Health grant examining melanoma immunogenicity. The presentation was titled, “Downregulation of Spliceosomal Proteins hnRNPH1 and H2 in WM266-4 Melanoma Cells Induces Immune Signaling” with results using NanoString method showing upregulation of immune pathways in melanoma cells. The abstract summarizing the presentation and the full list of authors/collaborators are below.
Downregulation of Spliceosomal Proteins hnRNPH1 and H2 in WM266-4 Melanoma Cells Induces Immune Signaling
Maab Sultan1*, Juan Diez2*, Keiran S.M. Smalley3, Vladimir Beljanski4, Lubov Nathanson5, and Dmitriy Minond1,2*
1 College of Pharmacy, Nova Southeastern University, 3321 College Avenue, Fort Lauderdale, FL 33314
2 Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, 3321 College Avenue, CCR r.605, Fort Lauderdale, FL 33314
3 Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.
4 Keeran Patel College of Allopathic Medicine and Cell Therapy Institute, 3321 College Avenue, CCR r.415, Fort Lauderdale, FL 33314
5 Keeran Patel College of Osteopathic Medicine and Institute for Neuro-Immune Medicine, 3321 College Avenue, CCR r.423, Fort Lauderdale, FL 33314
* – these authors contributed equally to the study
This study aims to determine the effect of hnRNPH1/H2 (H1/H2) downregulation on immune related genes in vitro. Due to the molecular heterogeneity of melanoma, it is difficult to treat it, which necessitates new approaches. We discovered compounds that selectively kill melanoma cells by binding to spliceosomal proteins hnRNPH1/H2. RNAseq of melanoma cells treated with H1/H2 siRNA showed upregulation of immune pathways. To validate this effect of genomic modulation of H1/H2 on immune gene expression, we used NanoString method. We treated both WM266-4 cell line and melanocytes with H1/H2 siRNA and scrambled siRNA to knockdown our target gene. Then, RNA was extracted and analyzed by NanoString. Analysis data of melanoma cell line showed a significant difference between RNA samples treated with scrambled and the one treated with siRNA in upregulating immune-related genes. In contrast, data of melanocytes revealed no significant difference between scrambled and siRNA samples and did not show upregulation of these genes. This implies the specificity of this response to melanoma cells.
In conclusion, we hypothesize that downregulation of spliceosomal proteins H1/H2 can upregulate immune-related genes, which in turn can improve melanoma patients’ survival. Consequently, H1/H2 can be targeted as a novel therapeutic approach.
Following up with Jeffrey Kibler PhD, Professor in the College of Psychology, about his NIH R15 grant we featured in our 2023 Research Report, links below
https://www.nova.edu/publications/dor-report/20/
Dr. Kibler and his team have been working on their NIH-funded project, titled “The Effects of a Cognitive Behavioral Healthy Lifestyle Intervention for Cardiovascular Risk Reduction in Posttraumatic Stress Disorder”, and offered this update:
“We have developed a great team of student researchers to assist with the project, and are now well on our way with data collection. Our preliminary findings indicate that the intervention we are testing has very good benefits for sleep and physical activity. We plan to seek additional funding that will support us in expanding the project, providing access outside Florida.”