Targeting glutamine metabolism to enhance the efficacy of radiopharmaceutical therapy

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Inhibition of glutamine metabolism or glutaminolysis is an exciting therapeutic strategy for glutamine-dependent cancers. Such a strategy may potentially avoid the complex upstream signaling pathways and directly prevent cancer cells’ energy production and required building blocks, starving them to death. Altered glutaminolysis is widespread across the disease spectrum of prostate cancer (PC) and renal cell carcinoma (RCC). The first step of glutaminolysis is mediated by glutaminase, which produces glutamate (Glu), an essential precursor for the biosynthesis of amino acids, nucleic acids, and energy production. In radiotherapy, where DNA damage is the central mechanism of cell death, cancer cells undergo metabolic reprogramming to enhance Glu utilization. Inhibition of glutaminolysis (Glni) has been increasingly used with radiotherapy to overcome radioresistance. However, the effect of targeted radiopharmaceutical therapy (RPT) on glutaminolysis remains unknown. To fill this gap, we will systematically evaluate the effect of prostate-specific membrane antigen (PSMA)-based radiopharmaceutical therapy (PSMA-RPT) on glutaminolysis using apporved, 177Lu-/225Ac-PSMA-RPT in experimental models of PC and RCC to deliver a mechanism-driven combination therapy. Since metastatic castration-resistant PC (mCRPC) is associated with high PSMA expression and PSMA is a Glu producing enzyme, PSMA has a critical role in mCRPC metabolism by utilizing a glutamine-independent metabolic pathway. Also, metastatic RCC is highly glutamine-dependent, and glutamine-deprived tumor neovasculature likely overexpresses PSMA to generate additional Glu to meet their high metabolic demand. Our preliminary data show that glutaminolysis is differently regulated in PSMA+ RCC tumors to address 225Ac-L1-induced DNA damage for their proliferation and growth. Additionally, our data revealed that Glni may upregulate PSMA levels in PSMA+ tumor models. Based on our preliminary data, we hypothesize that PSMA-RPT will significantly affect the glutaminolysis of PC and RCC, and Glni will expand the therapeutic window of PSMA-RPT. We have two Aims. In Aim 1, we evaluate the effect of PSMA-RPT on glutaminolysis as monotherapy and in combination with pharmacological (Aim 1a) and with genetic inhibition in PC and RCC cell lines (Aim 1b) to determine its role in DNA damage. In Aim 2, we will evaluate the effect of PSMA-RPT in selected preclinical models of PSMA+ PC and RCC in immunodeficient mice (Aim 2a) and immunocompetent mice (Aim 2b) as monotherapy and in combination with two selected inhibitors targeting the glutaminolysis pathways from Aim 1. We have established several human and mouse PSMA+ RCC and PC isogenic cell lines and a stable patient-derived RCC model for the proposed research. We will take advantage of our established PSMA-based research within our cancer center to expand the scope of PSMA-RPT for prostate and non-prostate malignancies. If successful, this project will uncover new insights into RTP-induced metabolic changes associated with DNA damage and will deliver mechanism-driven combination therapy beyond the existing paradigm.