PSMA targeting in metastatic castration-resistant prostate cancer: where are we and where are we going?

Giraudet, Anne-Laure; Kryza, David; Hofman, Michael S; Moreau, Aurélie; Fizazi, Karim; Fléchon, Aude; Hicks, Rodney J.

doi:10.1177/17588359211053898

Cited by 27 publications

(32 citation statements)

References 79 publications

(122 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PSMA is a non-soluble type 2 integral membrane protein with carboxypeptidase activity, expressed on the apical surface of endothelial cells [ 40 , 54 ]. PSMA is weakly expressed in normal prostate tissue but overexpressed in metastatic prostate cancer and is present in >80% of men with prostate cancer [ 37 , 40 , 55 ]. PSMA expression is also increased in androgen deprivation and is highest in high-grade and castration-resistant prostate cancer (CRPC) [ 55 , 56 ], and it could be used as a target for metastatic prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Peptide Modification Diminishes HLA Class II-restricted CD4+ T Cell Recognition of Prostate Cancer Cells

Doonan

Amria

Bethard

et al. 2022

IJMS

View full text Add to dashboard Cite

Prostate cancer poses an ongoing problem in the western world accounting for significant morbidity and mortality in the male population. Current therapy options are effective in treating most prostate cancer patients, but a significant number of patients progress beyond a manageable disease. For these patients, immunotherapy has emerged as a real option in the treatment of the late-stage metastatic disease. Unfortunately, even the most successful immunotherapy strategies have only led to a four-month increase in survival. One issue responsible for the shortcomings in cancer immunotherapy is the inability to stimulate helper CD4+ T cells via the HLA class II pathway to generate a potent antitumor response. Obstacles to proper HLA class II stimulation in prostate cancer vaccine design include the lack of detectable class II proteins in prostate tumors and the absence of defined class II specific prostate tumor antigens. Here, for the first time, we show that the insertion of a lysosomal thiol reductase (GILT) into prostate cancer cells directly enhances HLA class II antigen processing and results in increased CD4+ T cell activation by prostate cancer cells. We also show that GILT insertion does not alter the expression of prostate-specific membrane antigen (PSMA), an important target in prostate cancer vaccine strategies. Our study suggests that GILT expression enhances the presentation of the immunodominant PSMA459 epitope via the HLA class II pathway. Biochemical analysis showed that the PSMA459 peptide was cysteinylated under a normal physiologic concentration of cystine, and this cysteinylated form of PSMA459 inhibited T cell activation. Taken together, these results suggest that GILT has the potential to increase HLA class II Ag presentation and CD4+ T cell recognition of prostate cancer cells, and GILT-expressing prostate cancer cells could be used in designing cell therapy and/or vaccines against prostate cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Peptide Modification Diminishes HLA Class II-restricted CD4+ T Cell Recognition of Prostate Cancer Cells

Doonan

Amria

Bethard

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…This signaling process seems specific to cancer cells, as in normal cells, a relatively rapid washout takes place. Abusing this feature in cancer cells that have increased PSMA ligand uptake, targeting PSMA by radioligand therapy or by immunotherapy has become an emerging therapeutic approach to treat mCRPC [ 173 , 174 ] .…”

Section: Emerging Treatments Targeting Mcrpcmentioning

confidence: 99%

“…In addition to its significantly high expression in mCRPC, PSMA has a large extracellular domain which makes it an ideal target for immune agents [ 174 ] . Several approaches for PSMA-targeted immunotherapy exist including chimeric antigen receptor T cells, antibody-drug conjugates, bispecific T-cell engagers, and PSMA-directed vaccines.…”

Section: Emerging Treatments Targeting Mcrpcmentioning

confidence: 99%

Drug resistance in metastatic castration-resistant prostate cancer: an update on the status quo

Yehya¹,

Ghamlouche²,

Zahwe³

et al. 2022

Cancer Drug Resist

View full text Add to dashboard Cite

Prostate cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men globally. Despite improvements in the diagnosis and treatment of PCa, a significant proportion of patients with high-risk localized disease and all patients with advanced disease at diagnosis will experience progression to metastatic castration-resistant prostate cancer (mCRPC). Multiple drugs are now approved as the standard of care treatments for patients with mCRPC that have been shown to prolong survival. Although the majority of patients will respond initially, primary and secondary resistance to these therapies make mCRPC an incurable disease. Several molecular mechanisms underlie the development of mCRPC, with the androgen receptor (AR) axis being the main driver as well as the key drug target. Understanding resistance mechanisms is crucial for discovering novel therapeutic strategies to delay or reverse the progression of the disease. In this review, we address the diverse mechanisms of drug resistance in mCRPC. In addition, we shed light on emerging targeted therapies currently being tested in clinical trials with promising potential to overcome mCRPC-drug resistance.

show abstract

“…A similar patient population was involved in a phase I trial of an another PSMA targeting ADC carrying a pyrrolobenzodiazepine (PBD) payload namely MEDI3726 [ 75 ], and while clinical responses were seen at higher doses, TRAEs limited the duration of treatment, preventing further dose escalation and ultimately resulting in the study’s discontinuation. Ever since the very recent success of targeted radioligand therapy in this setting [ 76 ], numerous non-radioactive PSMA-targeting approaches are being actively researched, including chimeric antigen receptor T cells (CAR-T), vaccines and the promising bispecific T cell re-directed therapy [ 77 ]. Overall, although biologically appealing, the early clinical data pertaining to PSMA-targeting ADCs indicate modest efficacy at the cost of significant toxicity.…”

Section: Adcs In Gu Malignanciesmentioning

confidence: 99%

Antibody-drug conjugates: beyond current approvals and potential future strategies

Menon

Parakh

Scott

et al. 2022

Exploration of Targeted Anti-Tumor Therapy

View full text Add to dashboard Cite

The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in recent years have fuelled the ongoing development of this class of drugs. These novel agents combine the benefits of high specific targeting of oncogenic cell surface antigens with the additional cell kill from high potency cytotoxic payloads, thus achieving wider therapeutic windows. This review will summarise the clinical activity of ADCs in tumour types not covered elsewhere in this issue, such as gastrointestinal (GI) and genitourinary (GU) cancers and glioblastoma (GBM). In addition to the ongoing clinical testing of existing ADCs, there is substantial preclinical and early phase testing of newer ADCs or ADC incorporating strategies. This review will provide selected insights into such future development, focusing on the development of novel ADCs against new antigen targets in the tumour microenvironment (TME) and combination of ADCs with immuno-oncology (IO) agents.

show abstract

PSMA targeting in metastatic castration-resistant prostate cancer: where are we and where are we going?

Cited by 27 publications

References 79 publications

Peptide Modification Diminishes HLA Class II-restricted CD4+ T Cell Recognition of Prostate Cancer Cells

Peptide Modification Diminishes HLA Class II-restricted CD4+ T Cell Recognition of Prostate Cancer Cells

Drug resistance in metastatic castration-resistant prostate cancer: an update on the status quo

Antibody-drug conjugates: beyond current approvals and potential future strategies

Contact Info

Product

Resources

About