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U-M RADIOLOGY LEADS IN BREAKTHROUGH THERANOSTICS TREATMENT AND RESEARCH
Thanks to rapid expansion in the commercialization of diagnostic and therapeutic radiopharmaceuticals, U-M Radiology is part of an exciting new revolution in nuclear medicine known as “theranostics”.
“The speed of this growth has been staggering,” said Peter J. H. Scott, Ph.D., Professor of Radiology and Director of the Division of Nuclear Medicine and the Cyclotron and Radiochemistry Facility. “We didn’t really have the infrastructure or people to do therapy clinical trials in the past as there was little demand. Now we’ve got hundreds of companies asking if we can host them here and we’re partnering with Rogel Cancer Center to put a dedicated Theranostics Clinical Trial team in place.”
“Theranostics” is an amalgam of the words “therapy” and “diagnostics”. It refers to a type of personalized cancer treatment where a specialized diagnostic positron emission tomography (PET) scan determines the stage of the cancer, then the radioisotope is changed to a very similar molecule with a therapeutically useful radiation emission that can treat the cancer.
“If we can see it on a PET scan, it means that on a molecular level the cancer has the receptor expression that we need to get the radioactive medication into the cancer cells and give radiation treatment,” said Ka Kit Wong, M.D., Professor and Director of the Nuclear Medicine Therapy Clinic.
“One of the strongest advantages of theranostics is it’s a systemic treatment. So, if you see it on the PET scan and you inject the theranostic radioactive medication intravenously, it goes to every site of metastasis seen on the PET scan and treats all the disease at the same time.”
From radioisotopes to modern theranostics
U-M Radiology has a long history of using radioactive medications to help patients with cancer. In fact, nuclear medicine at U-M has been involved with theranostics since the beginning, though it did not bear that name 70 years ago when radioactive iodine therapies first began.
In the 1940s, William H. Beierwaltes, MD, began working with radioisotopes to treat thyroid cancer before nuclear medicine was even a discipline. He was one of a handful of physicians who attended a landmark meeting on the medical uses of radioisotopes offered by the Atomic Energy Commission (AEC) at the Oak Ridge, TN National Lab.
When he returned to Ann Arbor, Beierwaltes steered efforts to research radioisotopes to diagnose a variety of different malignancies. He eventually became the university’s first division director of Nuclear Medicine, helping the university acquire additional hospital space, a PET scanner, cyclotron, radiochemistry laboratories and personnel.
Radium-223 (Xofigo), approved for treatment of osseous metastases in prostate cancer in 2013, was the first agent in the modern era of theranostics and the first proven to improve longevity in cancer patients. Then lutetium-177 Dotatate, or Lutathera, was approved by the U.S. Food and Drug Administration (FDA) in 2018 for the treatment of neuroendocrine tumors. The latest theranostics development occurred in 2022 with lutetium-177 tagged prostatespecific membrane antigen (PSMA), or Pluvicto, for stage IV prostate cancer.
While the early diagnostics were developed by academic medical centers like U-M, the pharmaceutical industry was reluctant to market radioactive drugs in the past. That began to change with passage of the FDA Modernization Act of 1997. Among other things, the series of bills were intended to speed up the development of new pharmaceuticals, giving the industry a clear pathway to theranostics research and approval. This development and numerous acquisitions in the industry combined to fuel the surge.
“What’s happened since then is dozens of companies have spun out of oncology and biotech,” Scott explained. “So, there’s billions of dollars of pharma money and venture investment moving around in nuclear medicine in a way that’s just never happened before, and hundreds of theranostic agents are now in clinical trials.”
In addition to cancer treatment, Scott adds that imaging of amyloid plaques and tau tangles in the brain has been pivotal to the approval of anti-amyloid immunotherapies in the last few years for Alzheimer’s disease. While the therapies are not radioactive, like they are for cancer, the diagnostic agents are. “We were involved at the very start of this field 20 years ago and have been very big players building the dementia diagnostics that we have today,” says Scott.
Using theranostics to fight the second-leading cause of cancer death in men
Lutathera is available at University Hospital, and Pluvicto is available at both University Hospital and Brighton Center for Specialty Care. U-M has received about 500 referrals for Lutathera since it was approved seven years ago to treat rare, hormonally active tumors known as neuroendocrine neoplasms. By contrast, Pluvicto referrals have surpassed 300 in only a few years, because prostate cancer is much more common. But Pluvicto is only appropriate for a subset of men with prostate cancer.
“We have to be very realistic about the way we set patients’ expectations,” says Dr. Wong. “Information based on rigorous scientific studies is what’s conveyed to the patient. We do not highlight unrealistic effectiveness of a treatment, rather it is important to communicate that these are palliative treatments, not curative treatments.”
For the initially approved indication, which included some patients with a high metastatic disease burden, Pluvicto increased life expectancy for four months on average, although each individual responds very differently from the next and some have lived for years following Pluvicto therapy. Patients also experience fewer side effects and shorter administration times via intravenous injections with up to six total cycles, meaning Pluvicto is better tolerated compared to traditional chemotherapy. In the original treatment paradigm, Pluvicto was a “last resort” drug. Until very recently, men with Stage IV prostate cancer had to undergo traditional chemotherapy before they were eligible for Pluvicto treatment.”
“What ends up happening is many of these patients are older men who get really knocked down by the chemotherapy,” said Meghan Doyle, RN and Coordinator of the Nuclear Medicine Therapy Clinic. “So when we’re requiring chemotherapy to be given first, sometimes it really takes a toll on their body and our Pluvicto therapy might not be as effective, or it might have too many side effects that they probably would not have encountered otherwise.”
However, the FDA just approved Pluvicto for use prior to chemotherapy at the end of March, 2025. “I think that will open the floodgates for many more prostate cancer patients we will be able to treat,” said Doyle. The Therapy Clinic team, including Doyle and lead technologist Pete Siekierski CNMT, is already preparing for the next wave.
New theranostics research underway at U-M
The Division of Nuclear Medicine is creating a dedicated team to manage theranostics research, sponsored by Radiology and Rogel Cancer Center leadership. With more internal and sponsored theranostics research underway, renowned experts will steward these clinical and diagnostic trials through the onboarding process at U-M, coordinating the various stakeholders involved, including oncologists, radiologists and nuclear medicine physicians, technologists, physicists, advanced practitioners, clinical care coordinators, nurses and radiochemists, in order to make these cutting-edge experimental therapeutics available to our patients with cancer.
One investigational study led by Associate Professor Benjamin Viglianti, MD PhD, is applying the theranostics principle to a wide range of cancer types by focusing on a new target for cancer treatment known as fibroblast activation protein inhibitor or FAPI, which is expressed in dozens of different cancers.
“I’m very excited to see theranostics applied to a wide range of cancer types,” Dr. Wong said. “Because the landscape is changing so quickly, the numbers of patients who need these theranostic treatments will be increasing almost exponentially. We need to train the next generation of doctors to be able to meet the clinical need.”
Yuni Dewaraja, PhD, is a Professor in Nuclear Medicine whose work is almost fully funded by research grants from the National Institute of Health, and more recently from industry. She is the Principal Investigator on multiple grants but is especially interested in how to personalize the radioactive dose on an individual patient basis to optimize their care. Her research focuses on dosimetry, which is the measurement and calculation of the ionizing radiation dose that is absorbed in the human body. Her group has developed methods and software based on Monte Carlo simulation to do highly patient-specific dosimetry calculations, starting with each patient’s nuclear medicine images. Known as Dose Planning Method for Radiopharmaceutical Therapy (DPM_RPT), this technology is now available with GE HealthCare’s MIM Software.
“Right now, what we’re doing is one-size-fits-all therapy,” Dewaraja said. “So, if someone comes to us with prostate cancer, they’ll get six doses of Pluvicto. But is that the best way to be doing this? We are trying to reduce the number of cycles -- not just for the sake of reducing, but we think it works better if you give more radiation at the beginning of the treatment period. Our dosimetry calculations have shown that the radiation energy deposited in the tumor is higher in cycle one than in subsequent cycles.” Based on these findings, Dr. Dewaraja was recently funded to start a clinical trial with dose escalation in the first cycle while reducing the total number of cycles.
Dr. Scott is particularly interested in alpha therapies. Both Pluvicto and Lutathera are beta emitters. In some cases, cancers can become resistant to these drugs, which cause single strand DNA damage that cells can learn how to repair. In such situations, alpha emitters such as actinium-225 (which Scott refers to as “a cluster bomb” for cancer), could be used. Alpha emitters cause double strand DNA breaks that cancer cells are highly unlikely to become resistant to.
The potential that lies in these areas of research and the exciting new developments in theranostics only serve to further improve the care that patients with cancer receive at Michigan Medicine.
“I think our biggest strength here is the total care that our cancer patients receive,” said Scott. “Radiology has partnerships with the medical oncology groups, urology, urologic oncology, endocrinology, surgery, and radiation oncology. It’s all the folks we have throughout the Cancer Center and throughout Michigan Medicine that makes us a powerhouse, providing the total care package to these patients who come to us for cancer treatments.”
