Maximizing tumor responses to targeted radiotherapy with a conditionally activated membrane binding probe

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 β- (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.