• Prostate-specific membrane antigen, PSMA

    Prostate-specific membrane antigen (PSMA) is a 100 kDa type II transmembrane glycoprotein. High levels of PSMA expression are found on the membranes of aggressive types of tumor endothelial cells, prostate cancer, and other human cancers. 68Ga-PSMA-11, which significantly improves the detection of cancer cells, is the first FDA-approved agent for the imaging of PSMA-positive lesions via positron emission tomography (PET). Thus, this compound provides a more effective selection strategy for the identification of prostate cancer patients who may benefit from PSMA-targeted therapy. The recent FDA approval of 177Lu-PSMA-617 has indeed demonstrated promising results from PSMA-targeted radiopharmaceutical therapy (RPT) targeting patients with metastatic castration-resistant prostate cancer (mCRPC). The use of first generation PSMA targeted RPT has been limited in advanced prostate cancer due to concerns related to potential radiation toxicity. Thus, PSMA appears to be a good theranostic target meriting further research and development.

    1.S Boinapally. et al. (2021) Sci Rep. 11:7114

    2.U Hennrich.  et al. (2021) Pharmaceuticals (Basel). 14:713

    3.DP Petrylak. et al. (2019) Prostate. 76:604

  • Dual-Targeting Somatostatin Receptor 2 (SSTR2) and Cholecystokinin B Receptor (CCKBR/CCK2R)

    Somatostatin type 2 receptor (SSTR2) and Cholecystokinin 2 receptor (CCK2R) are  GPCRs that are aberrantly regulated in various tumors. It has been well established that SSTR2 is highly and broadly overexpressed in certain neuroendocrine tumors (NETs). Synthetic molecules that mimic the native SSTR2 ligand, somatostatin, have been successfully developed and approved as a theranostic-therapuetic pair, (Netspot® (68Ga-DOTATATE) and Lutathera® (177Lu-DOTATATE), for detecting and treating gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In addition, SSTR2 is also overexpressed in small cell lung cancer (SCLC) as well as medullary thyroid carcinoma (MTC) and SSTR2-targeted radiotherapy has shown promise for the treatment of both cancers. However, the level and breadth of clinical activity leaves room for improvement to address unmet medical need. Like SSTR2, CCK2R is overexpressed in SCLC, MTC and certain NETs and 177Lu-PP-F11N, an analog of the native ligand of CCK2R, has demonstrated specific and high tumor uptake in MTC patients. Importantly, SSTR2 and CCK2R are overexpressed in a complementarily and/or overlapping manner in SCLC, MTC and NETs tumors. This provides rationale for dual-targeting with a SSTR2/CCK2R therapeutic. Using our dual-targeting vector, FL-031, we aim to address the high unmet medical need in patients with SCLC, advanced MTC and NETs whose tumors are SSTR2-negative/low and are resistant or refractory to Lutathera®.

  • Neurotensin receptor type 1, NTSR1

    Neurotensin receptor type 1, NTSR1 (also called NTR-1) binds to neurotensin (NT), a 13-amino-acid peptide (or tridecapeptide) mainly secreted from the central nervous system and gastrointestinal tract. NTSR1 comprises 424 amino acids and belongs to a large superfamily (Class A) of 7-transmembrane (G protein-coupled) receptors. NTSR1 has high affinity towards NT. Signaling of the NT/ NTSR1 complex mediates multiple biological processes by G proteins that subsequently activate a phosphoinositide (PI)-derived second messenger system. Downstream signaling leads to the activation of Protein kinase C (PKC) and the enhancement of intracellular calcium mobilization, resulting in cell proliferation, survival, migration, and invasion. Importantly, higher expression of NT and NTSR1 were found in human cancers including pancreatic, lung, breast, prostate, and colon, among others. In vivo evidence suggests that NT/ NTSR1 signaling correlates with tumor growth. 

    1.S Nikolaou. et al. (2020) Cell Commun Signal. 18:68

    2.Zherui Wu. et al. (2013) Front Endocrinol (Lausanne). 3: 184

    3.N Christou. et al. (2020) Cell Death Dis. 11: 1027

  • Guanylyl Cyclase C, GUCY2C/GCC

    Guanylyl Cyclase C (GUCY2C, also known as heat-stable enterotoxin receptor), is a 145 kDa type I transmembrane glycoprotein that is involved in cGMP biosynthesis. Endogenous ligands for GUCY2C, including guanylin and uroguanylin, are hormones that activate GUYC2C, resulting in the regulation of cell dynamics and homeostatic equilibrium of proliferation, metabolism, and differentiation. They are also involved in defending against mutational, chemical, and inflammatory intestinal injury. GUCY2C expression is restricted to intestinal epithelial cells, and overexpression of GUCY2C is mainly found in colorectal cancers, esophageal, gastric, and pancreatic tumors. The overexpression of GUCY2C has been demonstrated to correlate with poor prognosis, and increased risk of metastasis. Targeting GUCY2C with radiopharmaceuticals provides an attractive therapeutic option for metastatic colorectal cancer in humans.

    1.Erik, S. et al. (2016) Mol. Pharmacol. 90 : 199

    2.D Lan. et al. (2016) Sci Rep. 6 : 25034

    3.Magee, MS. et al. (2018) Cancer Immuno Res. 6 : 509

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  • PSMA
  • NTSR-1
  • GCC