jaskula sztul portrait high res200x150Division of Breast and Endocrine Surgery Assistant Professor Renata Jaskula-Sztul, Ph.D., has won her third NIH R21 grant in two years. The newest R21 grant will fund her project, “Targeted neuroendocrine cancer therapy using Verrucarin A.”

Jaskula-Sztul serves as a principal investigator alongside Xiaoguang (Margaret) Liu, Ph.D., associate professor in the UAB Department of Biomedical Engineering.  The experimental support for this successful project was provided by Department of Surgery Researcher V Jason Whitt, Ph.D., and doctoral student Yingnan Si in the Department of Biomedical Engineering Liu Lab. 

According to grant authors, some neuroendocrine (NE) cancers frequently metastasize, or spread, to the liver. Despite various complex management strategies for NE liver metastases, surgery is currently the only treatment that offers potential for cure.

Authors propose an unlikely source for treating NE metastasis– Verrucarin A–a natural compound originating from marine sponges. This compound was identified in a high-throughput screening of na­tural molecules–primary and secondary metabolites of marine invertebrates–in collaboration with James McClintock, Ph.D., UAB Endowed Professor of Polar and Marine Biology, and Bill Baker, Ph.D., USF Professor of Chemical Ecology of Antarctic Invertebrates.

Researchers believe that Verrucarin A, VC-A is capable of inhibiting NE cancer cell proliferation and altering malignant phenotype. Preliminary studies suggest that the Verrucarin A, VC-A is capable to induce the apoptotic response, or programmed cell death, in some NE cancer cells.

The Science Behind It

The preliminary studies using NE cancer cell lines and human xenografts indicated that anti-SSTR2 mAb can effectively and specifically bind to NE cancer and the conjugation of SSTR2 mAb with the drug delivery vehicle – exosomes, did not change the targeting efficacy. Moreover, authors have shown that VC-A is capable to induce the apoptotic response in NE cancer cells in low nanomolar concentrations.

To improve therapeutic efficacy, authors propose to formulate the drug candidate in the exosomes, which are equipped with the antibody that specifically binds to somatostatin receptor 2 (SSTR2) overexpressed on the surface of NE cancer cells. Such anti-SSTR2 mAb-Exo-VC-A therapeutic can selectively deliver a lethal agent to tumor cells and minimize side effects to patients.

To delineate the antitumor efficacy of the targeting delivered VC-A, researchers will use the in vitro NE cancer cell cultures and the in vivo preclinical mouse model of liver metastases. If the anticancer efficacy will be confirmed in the preclinical models, this will be the first exosomes-facilitated targeted therapy for NE cancers.

The Implications

Jaskula-Sztul is delighted that this could be the first exosomes-facilitated targeted therapy for NE cancers and that this approach shows promise in inhibiting NE cancer metastasis.

“The implications of this study are large– to potentially facilitate a self-destructive response for NE cancer cells brings hope to researchers and physicians aiming to improve treatment for NE cancers,” said Jaskula-Sztul. “Dr. Liu and I look forward to using the R21 funding to learn as much as we can about targeted neuroendocrine cancer therapy using Verrucarin A.”