Project Abstract:
The recent FDA approvals (Lutathera, Azedra, Pluvicto) and the swell of promising experimental agents in clinical
trials underscore the surging enthusiasm to investigate molecularly targeted radiotherapy (TRT) as a treatment
modality for cancers. However, tumor responses to TRTs are often transient and/or variable among patients.
Thus, there is an urgent unmet need to develop new strategies to maximize the therapeutic benefit of TRT for
cancer patients. For the past several years, the nuclear medicine field has prioritized developing low MW small
molecule or peptide radioligands (RLTs) that rapidly exit the bloodstream to minimize host toxicity. However,
tumoral responses to RLTs are limited by several factors, including heterogeneous target expression among
tumors, dissociation or degradation of ligand/receptor complexes, and incomplete target saturation due to low
mass doses and infrequent repeat dosing. Thus, exploring new strategies beyond RLTs for the tumoral delivery
of radioisotopes is a worthwhile goal.
We have approached this challenge by developing a new class of radiopharmaceuticals termed
“restricted interaction peptides” (RIPs) which are linear and unstructured low MW peptides that are internally
cleaved by a tumor endoprotease of interest to unmask a radiolabeled, helical membrane binding peptide. Once
liberated, the radiolabeled helical peptide immediately and irreversibly attaches to a nearby phospholipid
membrane in the tumor. Using PET, we have found that RIPs may have several properties advantageous for
TRT, including catalytic amplification of tumor uptake and long persistence of the radioisotope in tumors due to
the stability of the peptide/lipid membrane interaction. Thus, RIPs offer an unusual combination of the desirable
safety profile characteristic of a low MW RLT with a high tumoral uptake more typical of a large MW TRT.
Collectively, these findings provide a strong scientific rationale to test for the first time if radiolabeled RIPs can
be effectively leveraged to treat tumors. Over three specific aims, we will evaluate the antitumor effects of a
novel RIP termed “FRIP2” by coupling it to a representative ß- (Lu-177) or alpha (Ac-225) emitter. Furthermore,
we will translate 64Cu-FRIP2 into patients to test the safety, dosimetry, and pharmacokinetics of the platform
while also evaluating the feasibility of tumor targeting. In summary, this project represents the first use of a
conditionally activated membrane binding probe for TRT, which may overcome the well documented
shortcomings of conventional RLT.