Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling
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.
Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction
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.
Glutamine addiction: a new therapeutic target in cancer
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.
Single-cell analysis of localized prostate cancer patients links high Gleason score with an immunosuppressive profile
BACKGROUND:Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry. METHODS:Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa). RESULTS: TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers. CONCLUSIONS:T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.
Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial [Comment]
IMPORTANCE/UNASSIGNED:Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination. OBJECTIVE/UNASSIGNED:To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021. INTERVENTIONS/UNASSIGNED:All patients in phases 1b and 2 received avelumab plus talazoparib. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers. RESULTS/UNASSIGNED:A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03330405.
Technology-enhanced AcceleRation of Germline Evaluation for Therapy (TARGET): A randomized controlled trial of a pretest patient-driven webtool vs. genetic counseling for prostate cancer germline testing
BACKGROUND:Germline testing has an increasingly important role in prostate cancer care. However, a relative shortage of genetic counselors necessitates alternate strategies for delivery of pre-test education for germline testing. This study, funded by the Prostate Cancer Foundation, seeks to address the need for novel methods of delivery of pre-test germline education beyond traditional germline counseling to facilitate informed patient decision-making for germline testing. METHODS:This is a two-armed randomized controlled trial (RCT) with a target enrollment of 173 participants with prostate cancer per study arm (total anticipated nâ€¯=â€¯346). Patients who meet criteria for germline testing based on tumor features, family history or Ashkenazi Jewish ancestry are being recruited from 5 US sites including academic, private practice and Veterans healthcare settings. Consenting participants are randomized to the interactive pretest webtool or germline counseling with assessment of key patient-reported outcomes involved in informed decision-making for germline testing. RESULTS:Participants complete surveys at baseline, after pretest education/counseling, and following disclosure of germline results. The primary outcome of the study is decisional conflict for germline testing. Secondary outcomes include genetic knowledge, satisfaction, uptake of germline testing, and understanding of results. CONCLUSION/CONCLUSIONS:Our hypothesis is that the web-based genetic education tool is non-inferior to traditional genetic counseling regarding key patient-reported outcomes involved in informed decision-making for germline testing. If proven, the results would support deploying the webtool across various practice settings to facilitate pre-test genetic education for individuals with prostate cancer and developing collaborative care strategies with genetic counseling. CLINICALTRIALS/RESULTS:gov Identifier: NCT04447703.
The Impact of Androgen Deprivation Therapy on COVID-19 Illness in Men With Prostate Cancer
BACKGROUND:TMPRSS2, a cell surface protease regulated by androgens and commonly upregulated in prostate cancer (PCa), is a necessary component for SARS-CoV-2 viral entry into respiratory epithelial cells. Previous reports suggested a lower risk of SARS-CoV-2 among PCa patients on androgen deprivation therapy (ADT). However, the impact of ADT on severe COVID-19 illness is poorly understood. METHODS:We performed a multicenter study across 7 US medical centers and evaluated patients with PCa and SARS-CoV-2 detected by polymerase-chain-reaction between March 1, 2020, and May 31, 2020. PCa patients were considered on ADT if they had received appropriate ADT treatment within 6 months of COVID-19 diagnosis. We used multivariable logistic and Cox proportional-hazard regression models for analysis. All statistical tests were 2-sided. RESULTS:We identified 465 PCa patients (median age = 71â€‰years) with a median follow-up of 60â€‰days. Age, body mass index, cardiovascular comorbidity, and PCa clinical disease state adjusted overall survival (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 0.68 to 1.98, Pâ€‰=â€‰.59), hospitalization status (HR = 0.96, 95% CI = 0.52 to 1.77, Pâ€‰=â€‰.90), supplemental oxygenation (HR 1.14, 95% CI = 0.66 to 1.99, Pâ€‰=â€‰.64), and use of mechanical ventilation (HR = 0.81, 95% CI = 0.25 to 2.66, Pâ€‰=â€‰.73) were similar between ADT and non-ADT cohorts. Similarly, the addition of androgen receptor-directed therapy within 30 days of COVID-19 diagnosis to ADT vs ADT alone did not statistically significantly affect overall survival (androgen receptor-directed therapy: HR = 1.27, 95% CI = 0.69 to 2.32, Pâ€‰=â€‰.44). CONCLUSIONS:In this retrospective cohort of PCa patients, the use of ADT was not demonstrated to influence severe COVID-19 outcomes, as defined by hospitalization, supplemental oxygen use, or death. Age 70â€‰years and older was statistically significantly associated with a higher risk of developing severe COVID-19 disease.
Germline APC (I1307K) mutation and clinical outcomes in prostate cancer [Meeting Abstract]
Background: The germline I1307K mutation in the adenomatous polyposis coli (APC) gene is a well known alteration identified in approximately 6% of the Ashkenazi Jewish population. Individuals with this mutation have an increased risk of developing colorectal and other cancers. The implications of the APC (I1307K) mutation in patients with prostate cancer are unknown. We sought to determine the clinical outcomes of patients with prostate cancer and the germline APC (I1307K) mutation.
Method(s): We retrospectively reviewed records from New York University and Johns Hopkins University to identify patients with the APC (I1307K) mutation. Eligibility criteria included the identification of the mutation either on germline or somatic tissue testing (when germline testing was not available). Aggressive variant prostate cancer (AVPC) was defined using previously established criteria including: presence of small cell histology, presence of exclusively visceral metastases, bulky prostate mass or lymphadenopathy, low PSA with high-volume ( > 20) bone metastases, neuroendocrine marker positivity or short interval ( < 6 months) to castration resistance. Combined somatic alterations in two or more of following genes were assessed: RB1, TP53, PTEN. These somatic alterations have been previously associated with AVPC. Descriptive statistics were used to summarize patient data.
Result(s): From 2016-2021, 13 patients with the germline APC (I1307K) mutation were identified. At the time of analysis 9 (69%) patients were alive. Most patients (7; 54%) had metastatic disease at presentation. Median PSA at diagnosis was 0.4 ng/mL (range: 0.4-20 ng/mL). The median time to castration resistance among those receiving hormonal therapy was 9 months (range: 3-13 months). Presence of small cell histology was found on initial biopsy in 3 patients and on subsequent biopsy in 1 additional patient (31% overall). Bulky prostate mass or lymphadenopathy was found in 3 (23%) patients. There were 2 (15%) patients who had low PSA with high-volume bone metastases. Four (31%) patients had radiographic progression with no concordant PSA increase. Clinically-defined AVPC was found in 7 (54%) patients and in 100% of those patients with metastatic disease. Combined somatic alterations in two or more of RB1, TP53 or PTEN were identified in 3 (23%) patients.
Conclusion(s): Prostate cancers that develop in the presence of the germline APC (I1307K) mutation appear to be enriched for clinically-defined and molecularly-defined AVPC. Several of these patients demonstrated small cell histology and PSA-independent progression, higher than the expected background rate. This raises the hypothesis that the germline APC (I1307K) mutation influences the somatic genomic and/or epigenomic landscape of prostate cancer. Larger studies to validate the increased risk of AVPC in APC (I1307K) carriers, and to elucidate the somatic alteration landscape in these patients, are ongoing
A phase 1/2 multicenter investigator-initiated trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC). [Meeting Abstract]
History of cancer is associated with increased platelet activity and atherothrombosis in patients with peripheral arterydisease [Meeting Abstract]
Background : Cancer and peripheral artery disease (PAD) share common risk factors and are frequently coprevalent. Platelets are culprits in the pathogenesis of PAD and mediators of arterial cardiovascular events. The association between platelet activity and cardiovascular events in patients with versus without cancer is uncertain. Aims : To investigate if cancer history is associated with platelet activity and incident cardiovascular events in a cohort of patients with PAD. Methods : 289 patients with PAD undergoing lower extremity revascularization enrolled in the Platelet Activity and Cardiovascular Events (PACE) study were followed longitudinally for a median of 18 months. Prior to revascularization, patients had platelet activity measured via light transmission aggregometry in response to ADP, collagen, epinephrine, and serotonin. The primary clinical outcome was myocardial infarction (MI). Other endpoints were MI/stroke and major adverse cardiovascular event (MACE; MI/stroke/death). Results : 64 patients (22.1%) reported a cancer history, 10 (15.6%) with metastatic and 10 (15.6%) with active cancer. Patients with (versus without) cancer history were older, less often Hispanic, and less frequently current smokers ( P < 0.05 for each). There was no difference in prevalent diabetes, coronary artery disease, hypertension, or antiplatelet therapy between groups. Platelet aggregation in response to submaximal ADP (0.4 muM, 1.0 muM), collagen (0.2 mug/ml, 1.0 ug/ml), and serotonin (10 muM) was higher in patients with versus without cancer history. Consistently, patients with cancer history experienced more incident MI (18.8% vs. 7.6%, P = 0.02), MI/stroke (25.0% vs. 9.3%, P = 0.002), and MACE (35.9% vs. 22.2%, P = 0.04). After adjustment for age, sex, race/ethnicity, smoking, diabetes, prior stroke, CAD, revascularization procedure, and antiplatelet therapy, patients with cancer history were at higher hazard for MI, MI/stroke, and MACE (Figure). The association between cancer and thrombotic events was most apparent in patients with metastatic and active cancer (Figure). Conclusions : In patients with PAD, cancer history was associated with increased platelet aggregation and risk for arterial thrombotic events