A Novel Triple Synergistic Therapeutic Framework for Addressing PRRT Resistance and Immunological Paradox in Grade 3 Neuroendocrine Tumors (NETs)

Abstract

Peptide Receptor Radionuclide Therapy (PRRT) Lu-177 DOTATATE resistance in well-differentiated Grade 3 Neuroendocrine Tumors (NETs) is a type of acquired therapeutic resistance in well differentiated tumors involving downregulation of SSTR2 receptors on their surface rendering Lu-177 DOTATATE therapy ineffective as Lu-177 DOTATATE specifically targets SSTR2 receptor mostly overexpressed on the surface of NETs). Azacitidine is a methyltransferase inhibitor which acts as hypomethylation agent and inhibits DNA methylation, preventing silencing of genes responsible for SSTR2 receptor demonstrating positive results for restoration of SSTR2 activity in NETs in pre-clinical studies. Atezolizumab, is a well studied immune checkpoint anti PD-L1 inhibitor that restores T-cell activity but generally fails as single monotherapy (Success rate<10%). Peptide Alpha Nuclide Therapy generally is advised for PRRT therapy resistant patients where alpha nuclide therapy can directly penetrate and damage tumors specifically with minimal off-target toxicity. Azacitidine combined with atezolizumab and peptide alpha nuclide therapy can be utilized as a triple synergistic framework where Azacitidine restores SSTR2 which also might potentially alter immunological paradox associated with conversion from cold to hot tumor in NETs improving efficacy of alpha nuclide therapy and simultaneously Atezolizumab being an anti PD L1 inhibitor will be able to bind to immunologically hot tumor inhibiting T-cell metabolic exhaustion allowing T cells to target and attack tumors which can can potentially improve quality of life in grade 3 well-differentiated neuroendocrine tumor (NET) patients.