Faculty Bibliography

Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.

Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.

Most cancers depend on a high rate of aerobic glycolysis for their continued growth and survival. Paradoxically, some cancer cell lines also display addiction to glutamine despite the fact that glutamine is a nonessential amino acid that can be synthesized from glucose. The high rate of glutamine uptake exhibited by glutamine-dependent cells does not appear to result solely from its role as a nitrogen donor in nucleotide and amino acid biosynthesis. Instead, glutamine plays a required role in the uptake of essential amino acids and in maintaining activation of TOR (target of rapamycin) kinase. Moreover, in many cancer cells, glutamine is the primary mitochondrial substrate and is required for maintenance of mitochondrial membrane potential and integrity and for support of the NADPH production needed for redox control and macromolecular synthesis.

BACKGROUND:Prostate cancer is the most common form of male cancer and can initially be treated as a localized disease. Although the 5-year survival rate at diagnosis approaches 100 percent, a subset of patients will subsequently develop resistance to treatment. This may ultimately lead to metastatic castration resistant prostate cancer (mCRPC), for which the prognosis is much less favorable. The importance of the Wnt/β-catenin pathway in treatment-resistant prostate cancer has inspired efforts to exploit the interaction of β-catenin with its transcription binding partners as a therapeutic strategy for prostate cancer. METHODS:Peptoid-peptide macrocycles are attractive design scaffolds for disrupting protein-protein interactions. In this study, we evaluate a library of these macrocycles and demonstrate their selectivity for the β-catenin/TCF (T Cell Factor) interaction. RESULTS:Importantly, we show that the macrocycles do not significantly alter the binding of β-catenin to cell surface protein, E-cadherin. Our lead sequence, Macrocycle 13, (MC13) was also tolerant of modifications aimed to improve aqueous solubility while retaining activity. Herein, we demonstrate in vivo proof of principle for using peptidomimetic macrocycles to target the β-catenin/TCF interaction. Treated prostate cancer mouse xenografts show markedly diminished tumor growth and decreased levels of myc protein. MC13 also inhibits growth in an organoid model with genetic alterations frequently found in prostate cancer. Transcriptome analysis of prostate cancer cells treated with MC13 reveals downregulation of key pathways, including Wnt/β-catenin and c-myc. Furthermore, chromatin immunoprecipitation (ChIP) analysis shows reduced β-catenin at its target genes, axin2 and c-myc. CONCLUSION/CONCLUSIONS:Our findings underscore the therapeutic potential of peptoid-peptide macrocycle inhibition of β-catenin in prostate cancer.

PURPOSE/OBJECTIVE:To explore pragmatic approaches integrating MRI and PSMA-PET/CT for evaluating extraprostatic extension (EPE) of prostate cancer (PCa). METHODS:>12). Diagnostic performance was tested with receiver operating characteristic (ROC) curves and compared using DeLong and McNemar tests. RESULTS:>12 among which 87.5% (7/8) were corrected upgraded and had pathological EPE. CONCLUSION/CONCLUSIONS:Several pragmatic approaches were explored for integrating MRI and PSMA-PET/CT to assess EPE in PCa. Combining morphological information from MRI and PSMA expression on PET/CT demonstrated good diagnostic performance and may be a simple pragmatic integrated method that can be used.

OBJECTIVES/OBJECTIVE:Prostate-specific membrane antigen (PSMA)-PET/CT has become integral to management of prostate cancer; however, PSMA-avid rib lesions pose a diagnostic challenge. This study investigated clinicopathological and imaging findings that predict metastatic etiology of PSMA-avid rib lesions. MATERIALS AND METHODS/METHODS:), miPSMA score), CT features (sclerotic, lucent, fracture, no correlate), other sites of metastases, and primary tumor findings. A composite reference standard for rib lesion etiology (metastatic vs non-metastatic) based on histopathology, serial imaging, and clinical assessment was used. RESULTS:, miPSMA), more commonly involved multiple ribs, and were more often sclerotic (p < 0.01); lucency/fractures were only seen in benign lesions. CONCLUSION/CONCLUSIONS:Several imaging and clinicopathological factors differed between PSMA-avid metastatic and benign lesions. Isolated rib lesions without other sites of metastasis are almost always benign. Careful assessment of CT features can help diagnose benign lesions. KEY POINTS/CONCLUSIONS:Question While prostate-specific membrane antigen (PSMA)-PET/CT has become integral to the management of prostate cancer, PSMA-avid rib lesions pose a diagnostic challenge. Findings Approximately a quarter of patients who had PSMA-avid rib lesions were metastatic. However, only 2.1% of them had isolated rib metastasis (without PSMA-avid metastases elsewhere). Clinical relevance Isolated PSMA-avid rib lesions are almost always benign when there is no evidence of metastatic disease elsewhere. Scrutinizing CT features can help diagnose benign PSMA-avid lesions with greater certainty.

BACKGROUND:Despite significant progress, prostate cancer remains a leading cause of death. Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are already approved for the treatment of hormone receptor-positive breast cancer, are undergoing extensive testing as monotherapy and in various combinations as a potentially valuable treatment modality in prostate cancer patients. Thus far, a limited number of these studies have published results, which have been largely disappointing. AREAS COVERED/METHODS:In this review, we describe the biologic rationale for the use of CDK4/6 inhibitors in prostate cancer, the existing clinical data describing their use in prostate cancer, and ongoing clinical trials of CDK4/6 inhibitors as monotherapy and in combination for the treatment of prostate cancer. In particular, we focus on possible resistance mechanisms that may be particularly relevant in prostate cancer patients, leading to de novo and acquired resistance, and we highlight novel strategies that can overcome this resistance. CONCLUSIONS:Current clinical trials are actively working to (1) refine the role of CDK4/6 inhibitors in prostate cancer patients; (2) develop new inhibitors of other cell-cycle targets, such as CDK2 and CDK7; and (3) explore novel combination therapies with inhibitors of other relevant pathways, such as PI3K or MAPK. Further genomic subtyping of advanced prostate cancer will likely shed light on the subsets of patients most likely to benefit from cell-cycle-targeted agents.

OBJECTIVE:To advocate for universal germline genetic testing (UGGT) in prostate cancer and provide practical recommendations for its implementation. METHODS:Although guidelines for germline genetic testing (GGT) in prostate cancer have progressed, usage remains limited and inconsistent due to barriers including access, cost, and variable guideline adherence. These issues prevent some patients with germline pathogenic/likely pathogenic variants from benefiting from risk assessment, precision therapies (e.g., PARP inhibitors, PD-1 inhibitors) and potential clinical trials. Despite these benefits, studies indicate that GGT use remains low, especially in prostate cancer care. The PROCLAIM trial (Shore et al., 2023) highlighted that nearly half of patients with pathogenic variants are missed under NCCN guidelines, particularly impacting non-white patients and those with incomplete family history data. Additional racial and socioeconomic disparities further hinder access and variant interpretation accuracy. Given these challenges, UGGT for all prostate cancer patients has been proposed to improve care equity and decision-making. In March 2024, prostate cancer experts convened to discuss strategies for UGGT implementation. RESULTS:The outcome of that meeting includes recommendations for integrating UGGT into oncology and urology practices and have been outlined in this paper. CONCLUSIONS:To maximize the benefits while mitigating the potential risks of UGGT, it is essential to address implementation details, including careful gene panel selection, VUS reporting and management, appropriate genetics follow-up, and seamless integration of test reports into EMRs for accessibility by patients and providers.

OBJECTIVES/OBJECTIVE:An increasing number of patients with prostate cancer (PCa) undergo assessment with magnetic resonance imaging (MRI) and prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT). This offers comprehensive multimodality staging but can lead to discrepancies. The objective was to assess the rates and types of discordance between MRI and PSMA-PET/CT for primary PCa assessment. MATERIALS AND METHODS/METHODS:Consecutive men diagnosed with intermediate and high-risk PCa who underwent MRI and PSMA-PET/CT in 2021-2023 were retrospectively included. MRI and PSMA-PET/CT were interpreted using PI-RADS v2.1 and PRIMARY scores. Discordances between the two imaging modalities were categorized as "minor" (larger or additional lesion seen on one modality) or "major" (positive on only one modality or different index lesions between MRI and PSMA-PET/CT) and reconciled using radical prostatectomy or biopsy specimens. RESULTS:Three hundred and nine men (median age 69 years, interquartile range (IQR) 64-75) were included. Most had Gleason Grade Group ≥ 3 PCa (70.9% (219/309)). Median PSA was 9.0 ng/mL (IQR 5.6-13.6). MRI and PSMA-PET/CT were concordant in 157/309 (50.8%) and discordant in 152/309 (49.1%) patients; with 39/152 (25.7%) major and 113/152 (74.3%) minor discordances. Of 27 patients with lesions only seen on MRI, 85.2% (23/27) were clinically significant PCa (csPCa). Of 23 patients with lesions only seen on PSMA-PET/CT, 78.3% (18/23) were csPCa. Altogether, lesions seen on only one modality were csPCa in 80.0% (36/45). CONCLUSION/CONCLUSIONS:MRI and PSMA-PET/CT were discordant in half of patients for primary PCa evaluation, with major discrepancies seen in roughly one out of eight patients. KEY POINTS/CONCLUSIONS:Question While both MRI and PSMA-PET/CT can be used for primary tumor assessment, the discordances between them are not well established. Findings MRI and PSMA-PET/CT were discordant in about half of the patients. Most prostate lesions seen on only one modality were significant cancer. Clinical relevance MRI and PSMA-PET/CT are often discordant for assessing the primary prostate tumor. Using both modalities for primary prostate tumor evaluation can provide complementary information that may substantially impact treatment planning.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.