Page 23 - ARNM-1-2

Advances in Radiotherapy
& Nuclear Medicine FAP-targeted RLT in cancer

survival rate despite the use of conventional therapies . the effect of FAP-TRT (RLT) on various malignancies.
[2]
Immunotherapy has ushered in a new era of tumor Preliminary results have demonstrated good safety across
treatment, demonstrating promising efficacy. However, all studies and effectiveness to different degrees [11-13] . This
the effectiveness of these treatments is hindered by several review summarizes the latest pre-clinical and clinical
obstacles, with drug resistance being a significant barrier findings regarding FAP-targeted RLT.
that reduces the efficacy of chemotherapeutic agents .
[3]
Therefore, it is imperative to explore novel and alternative 2. Non-radionuclide targeting of FAP as an
therapeutic approaches to address this challenge and antitumor therapy approach
improve treatments. Tumor tissues consist of tumor cells and the surrounding
Recently, targeted radioligand therapy (TRT) has TME. The TME plays a vital role in tumor growth,
gained significant momentum and emerged as a promising progression, metastasis, and treatment outcomes, making
avenue for treating various types of malignancies . TRT it indispensable for the development of malignant
[4]
[7]
is characterized by different β-emitting or α-emitting tumors . CAFs, which originate from normal fibroblasts
radionuclides of label-specific molecules, which are activated by tumor cells, are essential components of the
expressed or upregulated in tumors through the systemic TME. They contribute to tumor cell survival, invasion,
[14]
administration of a radioactive drug, allowing precise and metastasis . CAFs can also arise through processes
targeting of tumor sites and delivering radiation directly such as an epithelial-to-mesenchymal transition from non-
to the tumor while sparing healthy tissues and organs . fibroblastic cells or endothelial-to-mesenchymal transition
[5]
Peptide receptor radionuclide therapy (PRRT) has been from endothelial cells . Notably, CAFs exhibit diverse
[15]
widely recognized as a highly effective and well-tolerated functions, and while they often promote tumorigenesis,
treatment approach for patients with neuroendocrine specific subsets of CAFs have shown significant tumor-
tumors (NETs) and was approved by the US Food and suppressive effects .
[16]
Drug Administration (FDA) in 2017. Moreover, in an CAFs can express receptors such as FAP, platelet-derived
international, randomized, open-label phase III study growth factor receptor β, and CD10. Among these, FAP, a
(NCT03511664, available from https://clinicaltrials.gov/ type II transmembrane serine protease belonging to the
ct2/show/NCT03511664), Lu-PSMA-617 plus standard dipeptidyl peptidase 4 family , has attracted increasing
177
[17]
of care (SOC) treatment was a well-tolerated regimen. attention. Normal fibroblasts and tissues are characterized
This approach has improved radiographic progression- by the absence or low expression of FAP, making it a
free survival (rPFS) and prolonged overall survival (OS) promising target for imaging and treatment [18,19] . Various
compared to SOC alone in men with advanced-stage strategies targeting FAP have been investigated for the
prostate-specific membrane antigen (PSMA)-positive treatment of colorectal and non-small-cell lung carcinomas,
metastatic castration-resistant prostate cancer (mCRPC), including anti-FAP monoclonal antibodies , FAP-antigen
[20]
supporting its adoption as an SOC and receiving FDA vaccination , suppression of FAP enzyme activity , and
[22]
[21]
approval in 2022 . Nevertheless, the absence of pan-tumor chimeric antigen receptor-T (CAR-T) cells specifically
[6]
targets poses a challenge to the widespread adoption of targeting FAP . These therapies have been well-tolerated
[23]
TRT. Therefore, identifying pan-tumor targets is a key to and deemed safe. Another potential approach involves
successful TRT application. anti-cytokine therapies targeting interleukin-6, C-X-C
Cancer-associated fibroblasts (CAFs) are crucial and motif chemokine ligand 12, and transforming growth
abundant constituents of the tumor microenvironment factor-β (TGF-β). These therapies aim to reduce the
(TME) that plays a significant role in tumor progression, recruitment and activation of CAFs, thereby decreasing
including tumorigenesis, angiogenesis, metastasis, the secretion of cytokines and chemokines by CAFs . The
[7]
immunosuppression, and developing drug resistance . extracellular matrix (ECM) serves as a physical barrier to
[7]
CAFs exhibit high fibroblast activation protein (FAP) delivering tumor drugs. Strategies focusing on targeting
expression, while normal organs and tissues display either the production of ECM proteins or promoting ECM
no or low expression . Consequently, several small FAP degradation show promise in facilitating drug delivery
[8]
[24]
inhibitors (FAPIs) have been developed and used to and potentially enhancing cytotoxic effects in tumors .
visualize the tumor stroma by targeting FAP. FAPI has Among these approaches, AVA6000 stands out as a FAP-
demonstrated superiority over 18F-fluorodeoxyglucose activated prodrug of maytansinoid. It is expected to
( F-FDG) in diagnosing various tumors [9,10] , making it a possess enhanced tumor-killing effects while minimizing
18
novel method for tumor imaging and radioligand therapy. systemic side effects (NCT04969835, available from https://
Several pre-clinical and clinical studies have explored clinicaltrials.gov/ct2/show/NCT04969835). While several

Volume 1 Issue 2 (2023) 2 https://doi.org/10.36922/arnm.1667