Project title: PANNET Modeling, Mechanisms, and Experimental Treatment

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Description

Bibb and his team will develop a novel model of pancreatic NETs (pNETs) that features the capability to be turned on or off and to generate both functional and nonfunctional forms of pNETs. The research team will also explore the protein kinase Cdk5, which is implicated in pNETs and may control gene expression contributing to tumorigenesis.

What question will the researchers try to answer?

Our research will explore the mechanistic basis of pancreatic NET (pNET) tumorigenesis in order to identify new treatments that target these mechanisms.

Why is this important?

PNETs are the second most common pancreatic neoplasm. The majority of pNETs are metastatic at the time of detection and no curative adjuvant therapies exist. While gene mutations have been linked to some pNET cases, molecular treatment strategies based on these mutations have had limited success. Dr. Bibb’s team aims to identify additional drug targets and advance novel treatments for pNETs by identifying tumor-forming signaling mechanisms and using this information to more accurately model the disease.

What will researchers do?

The team will characterize cellular signaling in human pNETs, derive and study new models of the disease, and test new treatments in these models in the hopes that they may ultimately be translated to clinical application.

How might this improve the treatment of NETs?

By identifying druggable mechanisms and showing positive responses to drugs that target them in novel models, the hope is to advance new treatment approaches to the point that they can be tested in clinical trials.

What is the next step?

The goal is to derive large databases to mine for mechanisms of interest, validate these targets, and prove that they can serve as points of vulnerability for stopping neuroendocrine tumors. As one example, Dr. Bibb believes that the protein kinase called Cdk5 drives the formation of pNETs. He and his team also have novel drugs that are showing positive responses in their models and hope to advance the application of these and alternative compounds in preclinical studies to move these compounds towards clinical trials. At the same time, they are working to develop a system to detect biomarkers that may direct anti-Cdk5 therapy as a precision medicine approach. In other studies, they are modifying their model systems to be more amenable to experimental manipulation. Dr. Bibb plans to share all these reagents and tools with the NET research and health care communities to advance treatments and cures for NETs.

Outcomes:

The goal of this NETRF Accelerator Award funded research has been to advance our understanding of the causes and develop new treatment approaches for pancreatic neuroendocrine cancers (PanNETs) through 1) study of neoplastic intracellular signaling, 2) the generation and characterization of novel animal models of the disease, and 3( by testing new therapeutic approaches that target the novel tumorigenic mechanism we have discovered. In large part, we have accomplished these goals as summarized here, while opening new avenues of research that will meaningfully impact our understanding of this and other forms of neuroendocrine cancer and how it may be more effectively treated. We identified numerous novel mechanisms by which dysregulation of calcium homeostasis in pancreatic islet cells triggers loss of bioenergetic sensing, alters metabolism, and invokes cancer causing gene expression programs. This includes a novel epigenetic signaling mechanism on which intensive study is ongoing by which the aberrant activity of the protein kinase Cdk5 alters chromatin architecture to launch preneoplastic gene expression networks. We made the first inducible model of nonfunctional PanNETs, the most common form presenting by clinical patients. We used this model to delineate gene expression programs that overlapped directly with those of human tumors. This model is now being adapted for optical detection of tumor load and will be shared broadly with the NET research community. We showed that Cdk5 inhibitors that we discovered are effective as anti-PanNET therapy across multiple models of the disease. Our lead drug, MRT3-007 shows efficacy but a therapeutic window that is too narrow for advancement for clinical trials. Currently, we are conducting drug screens to identify a compound with a profile suitable for testing in patients. Thus, this award allowed us to make major advances toward understanding the causes and development of new treatments for PanNET and other NECs. This work continues even as this award has now expired.

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