The long road to the clinic

Positron Emission Tomography (PET) is a non-invasive imaging technology that uses a trace amount of a PET imaging agent (“probe”) to quantitatively and safely measure biochemical processes, including the cycle of disease initiation, progression, therapeutic intervention, and regression. PET is often referred to as “molecular imaging”; unlike clinical MRI and CT, which focus on structure, PET provides a real-time functional readout of the body. One of PET’s defining characteristics is its translational nature – what can be studied in cells and mice can also be studied in humans – providing a powerful tool to evaluate the biology of disease and guide the drug discovery process; a diagnostic cornerstone of personalized medicine.

Professor Julie Sutcliffe knows the road to the clinic well. Her formative academic years as a chemist provided a window into PET probe discovery and routine clinical production. Now, as a tenured professor of Internal Medicine and Biomedical Engineering at UC Davis, co-Director of The Center for Molecular and Genomic Imaging, and Director of the new Radiochemistry Research and Training Facility, Dr. Sutcliffe’s research efforts are focused on the design, synthesis, in vitro identification, and in vivo screening of targeted molecular imaging agents. Dr. Sutcliffe’s group embraces innovative technologies, having developed and automated rapid radiolabeling technologies for the incorporation of fluorine-18 into peptides, becoming the first to publish the application of “click “ chemistry in PET and develop a high-throughput approach to PET probe discovery.

As the principal investigator for grants funded by the National Institutes of Health and the Department of Energy, and a track record of successful and productive research projects and education, she recently spearheaded the partnership between UC Davis Health System, PETNET Solutions Inc., a wholly owned subsidiary of Siemens Medical Solutions USA, Inc., and the Northern California PET Imaging Center (NCPIC) to establish a facility on UC Davis’ Sacramento campus for research and training in radiochemistry and for the commercial production of radiopharmaceutical products used in PET.

Few scientists are better suited to discuss PET’s translational power, so we sat down with Dr. Sutcliffe to find out about her latest Exploratory IND submission and plans for the future.

Melissa Moore: First, congratulations on your recent FDA submission for an exciting novel PET probe! Tell us a little about the process.

Julie Sutcliffe: Thank you, it was a marathon…painful but we survived! I would like to say it was fun but…(smiles).

MM: So, good, but good to be done?

JS: Yes, definitely.

MM: When did the idea for this probe first emerge? How did you know this would be a great candidate for the clinic?

JS: We became interested in the target αvβ6 approx 14 years ago. Many of you have heard about integrins and the RGD peptides to target integrin αvβ3. We had a lot of experience of making peptides – basically my life as a Ph.D student – but at that time there was nothing developed to target the integrin αvβ6. It was the new kid on the block, and was found to be overexpressed on head and neck cancers. I was working with a head and neck surgeon before I came to the USA and he described the challenges of achieving clean margins in these patients and the need for a way to better image the disease.

Actually, it is an epithelial-specific cell surface receptor that is undetectable in healthy adult epithelium but is significantly upregulated in a wide range of epithelial derived cancers. This receptor is often localized to the invasive front and infiltrating edges of tumors and plays a key role in invasion and metastasis and its expression is often associated with poor prognosis. With the unique expression of αvβ6 being a predictor of decreased progression free survival (PFS), response rate (RR), and overall survival (OS) we, and others, believe that the silver lining of this negative correlation is the much-needed opportunity to utilize αvβ6 for both diagnostic and therapeutic measures. The high contrast between malignant and healthy tissue and the functional relevance of αvβ6, especially in those diseases with a more aggressive phenotype, together place αvβ6 squarely on an elite list of targets for which development of diagnostic and therapeutic compounds will be vital to the future management of a very wide range of invasive diseases…so as it turns out it’s pretty important in many cancers, like pancreatic, lung, colon, breast, prostate and is an indicator for poor prognosis. In other words, you really don’t want your tumor to have αvβ6.

My first grant to the NIH (NCI) to develop peptide based molecular imaging agents to target αvβ6 was funded in 2003 by NCI, so off we set to develop the imaging agent. We used rational and random approaches as little was known about the target and its binding ligand (there was no crystal structure, for example) and believe it or not we found our answer in part of the foot and mouth disease virus! Lots of synthesis, lots of modifications, lots of long days and late nights in the lab, lots of fun and a few tears along the way and here we are αvβ6 -BP here we go! ☺

MM: That’s definitely how scientific discovery goes, right? A lot of hard work and the refusal to give up on good ideas. What was it that Edison said?

JS: Oh, yes! Something like, “I have not failed. I've just found ten thousand ways that won't work”?

MM: That sounds right. So, you made it work! Can you share some key learning about preparing and submitting the IND package? What were the most challenging aspects of that process and how did you overcome them?

JS: Be prepared to get your hands dirty, especially if this is the first time your institution has done this. Be patient, it’s a lot of documentation. Don’t be afraid to ask for help. My friends at MSKCC, UCLA, and Wash U were lifesavers. Take off your research hat. Think about simplifying the chemistry early on so that you don’t have to make changes to the chemistry at the last minute to make it patient friendly. I’m hoping that the process is like riding a bike.

MM: Which means you never forget? Just get a little rusty in between?

JS: Yes! Hopefully the next one is even easier.

MM: I like to think of you as the Queen of Peptides. They’re definitely emerging as a powerful new class of PET probes and you were way ahead of the trend. What are some key features of peptides that make them great candidates for targeting disease?

JS: “Queen of peptides”, that’s a new one! I am usually referred to by many as “The princess”. But seriously, many peptide receptors are overexpressed in cancer, so we have a lot of targets and structures to choose from. Peptides are relatively easy to synthesize thanks to brilliant chemists such as Merrifield, the pioneer of solid-phase peptide synthesis. They are non-immunogenic and can be chemically modified to improve pharmacokinetics. They are also amenable to radiolabeling.

MM: Well, you wear many hats. Queen, princess – the entire royal court! Another amazing aspect of your lab is the way in which you embrace automation. You’re constantly forward thinking in your application of new tools to old problems. In what ways does automation affect your process?

JS: It’s definitely been helpful in removing operator error, improving reproducibility, and sparing the chemist an unnecessary radiation dose. Keeping my team safe and happy is critical.

MM: What role do you see the SOFIE Probe Network playing in the IND submission process?

JS: Currently there is no fully automated device to radiolabel peptides with fluorine-18. Method development and deployment to multiple sites is critical for multi-center trials. Sharing methods through the SPN would expedite development. The ability to cross reference tox and have rapid access to methods needed for IND applications would enable rapid deployment for multi-center trials. I’m excited to get going in the SPN!

MM: Me, too! What’s next for the Sutcliffe lab?

JS: We are excited to perform the first-in-human study. You’ve heard the phrase “bench to bedside and back again”, right? We expect to tweak a little more after we go into the clinic.

MM: Of course! The science is never quite done, right?

JS: Right. And if we are able to easily share methods and tox data, we will propose a multi-center trial. We have NIH funding to optimize the imaging agent further as well as develop the therapeutic partner for αvβ6. We also plan to use our combinatorial library screening strategies to identify new targets and develop new peptide probes. Not to mention a few graduations, a few weddings, a few bottles of champagne and having a LOT of FUN!