Life science
Medicine (diagnosis and treatment of cancer), Drug development

Novel targeted alpha therapy against cancer stroma
Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine
Assistant professor Tadashi Watabe
Researchmap https://researchmap.jp/twosaka2018?lang=en

Life science

Abstract
We have succeeded in developing a new concept radiotherapy
drug (actinium-labeled fibroblast-activating protein inhibitor ([225Ac]
FAPI-04)) targeting cancer-associated fibroblasts in cancer stroma. When it was administered to pancreatic cancer model mice,selective accumulation in tumors and tumor growth inhibition wereconfirmed (Fig. 1). Cancer-associated fibroblasts create the environment necessary for the growth of cancer cells and also serve asa barrier to prevent anti-cancer agents from reaching the cancer
cells. In this research, we have shown for the first time in the worldthat by attacking cancer with short-range radiation called alpharays, it suppresses the growth of cancer cells.

▍ Background & Results
Although the overall survival rate of cancer patients is improving, the 5-year relative survival rate of pancreatic cancer remains
at a fairly low level of 10%, limiting the effectiveness of existingtreatments. [225Ac]FAPI-04, which was successfully developed inthis research, can be administered to patients with intractable pancreatic cancer by targeting multiple metastatis. Furthermore, it has
been reported that FAP is expressed in many cancer types otherthan pancreatic cancer, and in the future, the effectiveness of treatment for other cancer types will be verified. We would like to go forclinical application as a therapeutic drug against broad types ofcancers.

Fig.1. (a) Human pancreatic cancer cells were grafted onto mice, which werethen given targeted alpha radiation therapy ([225Ac]FAPI04). Compared with mice
given a control treatment (black squares), mice given [225Ac]FAPI04 (open circles)
showed a marked decrease in tumor growth. (b) Mice were injected with diagnostic imaging probe ([64Cu]FAPI-04) to enable positron emission tomography(PET) imaging. The imaging shown here indicates uptake of 64Cu-FAPI-04 in thepancreatic cancer xenograft (arrow).

▍ Significance of the research and Future perspective
In recent years, treatment using alpha rays, which has a hightherapeutic radiation effect, has attracted attention. General alpha-ray therapies have targeted specific molecules that appear on
the surface of cancer cells. However, these molecules often differ
depending on the type of cancer, and the degree of expression
may differ at the site of metastasis. In addition, when performing
treatment targeting cancer cells, the stroma surrounding the cancer cells may act as a barrier, and the anticancer drug may not be
sufficiently distributed to the cancer cells. Especially in pancreaticcancer, since there are many components of this cancer stroma,
existing treatments often fail and become intractable, and a newtreatment strategy is required. Through joint research with theUniversity of Heidelberg in Germany, we have succeeded in developing a new radiotherapy drug targeting cancer-associated fibroblasts (CAFs), which are the main constituents of cancer stroma.
FAP (fibroblast activation protein) is strongly expressed in the CAFsof many cancers, while its expression in normal organs is low. In
this study, an intravenous administration of a FAP inhibitor ([225Ac]FAPI-04) labeled with the α-emitter actinium(225Ac) showed significant tumor growth suppression in pancreatic cancer model mice.
In the future, it is expected to become an epoch-making treatment
for intractable cancer including pancreatic cancer.

Fig. 2. Schema of cancer-associated fibroblasts (blue) and cancer cells (brown)in the cancer stroma: Therapeutic agent [225Ac] FAPI-04 (red circle) irradiates alpha rays from the stroma.

P a t e n t PCT/EP/2019/052952
Watabe, T; Liu, Y; Kaneda-Nakashima, K, et al. Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64Cu and 225Ac-Labeled FAPI-04 in
Pancreatic Cancer Xenograft Mouse Models. J Nucl Med. 2020 Apr; 61(4): 563-569. doi: 10.2967/ jnumed.119.233122.
Tr e a t i s eLiu, Y; Watabe, T; Kaneda-Nakashima, K, et al. Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac] FAPI-46 in a pancreatic cancer model. Eur J Nucl Med Mol Imaging. 2021 Sep 18. doi: 10.1007/s00259-021-05554-2.
URL https://resou.osaka-u.ac.jp/ja/research/2019/20191004_2
K e y w o r d targeted alpha therapy, pancreatic cancer, cancer stroma, actinium