Programs

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  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

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  Somatostatin Receptor 2 (SSTR2)

  Somatostatin type 2 receptor (SSTR2) belongs to the G-protein coupled receptor (GPCR) family that is 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). However, the objective radiographic response rate (ORR) for Lutathera® is 18% with nearly no treatment options after Lutathera®, and GEP-NETs only represents half of total NET incidents. Separately, SSTR2 is also overexpressed in small cell lung cancer (SCLC) and other tumor types, and SSTR2-targeted radiotherapy has shown certain efficacy for their treatment but still at very early development stages. Collectively, there is still sizable opportunities of SSTR2-targeted radiotherapies and associated significant unmet medical needs. With an Ac-225-based alpha-therapy that is targeted via our novel SSTR2 vector, we aim to expand the indication of SSTR2-targeted radiotherapies from GEP-NETs to other NET subtypes, SCLC and other SSTR2-postive indications whose tumors are SSTR2-medium/low expressed or resistant/refractory to Lutathera®. 
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  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