Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Abstract

Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.

Keywords: Chemotherapy; Gastro-entero-pancreatic neuroendocrine carcinoma; Immunotherapy; Molecular-targeted therapy.

Fig. 1

Characteristics and treatment of GEP-NET, GEP-NEC, and SCLC. For patients with GEP-NET, synthetic somatostatin analogs (SSAs) are used due to their favorable biology, including relatively low Ki-67, slow growth, and positive somatostatin receptor (SSTR) expression. Chemotherapy regimens recommended for advanced GEP-NETs and G3 GEP-NETs include streptozotocin-based, temozolomide-based, and platinum-based treatments. Molecular-targeted agents such as everolimus (Eve) and sunitinib (Sun) are also available, with Sun currently approved for pancreatic NETs only. Peptide receptor radionuclide therapy (PRRT) is an option for patients with progressive NETs expressing SSTR after first-line therapy. For patients with GEP-NEC, the standard first-line regimen remains cisplatin plus etoposide or cisplatin plus irinotecan. For patients with SCLC, the standard regimen consists of platinum-based chemotherapy combined with an immune checkpoint inhibitor (ICI) such as atezolizumab or durvalumab. NE, neuroendocrine; TFs, transcription factors

Fig. 2

Summary of potent therapeutic strategies for GEP-NEC. The potent approaches are composed of both neuroendocrine-specific and site-specific treatment. ADC, antibody–drug conjugate; BiTE, bispecific T-cell engager; CAR-T, chimeric antigen receptor-T cell therapy; PRRT, peptide receptor radionuclide therapy; HDAC, histone deacetylase; ICI, immune checkpoint inhibitor; DDR, DNA damage response. The “anti- “ means blockade of indicated molecule. The “α” includes other ICIs, chemotherapy, HDAC inhibitor, anti-angiogenic therapy, and DDR inhibitors targeting AURK, WEE1, ATR, ATM, AXL, CHK1, or PARP. The “β” includes other DDR inhibitors, and chemotherapy