Searched for: person:wised03
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Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling
Bluemn, Eric G; Coleman, Ilsa M; Lucas, Jared M; Coleman, Roger T; Hernandez-Lopez, Susana; Tharakan, Robin; Bianchi-Frias, Daniella; Dumpit, Ruth F; Kaipainen, Arja; Corella, Alexandra N; Yang, Yu Chi; Nyquist, Michael D; Mostaghel, Elahe; Hsieh, Andrew C; Zhang, Xiaotun; Corey, Eva; Brown, Lisha G; Nguyen, Holly M; Pienta, Kenneth; Ittmann, Michael; Schweizer, Michael; True, Lawrence D; Wise, David; Rennie, Paul S; Vessella, Robert L; Morrissey, Colm; Nelson, Peter S
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.
PMCID:5750052
PMID: 29017058
ISSN: 1878-3686
CID: 2758612
Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction
Wise, David R; DeBerardinis, Ralph J; Mancuso, Anthony; Sayed, Nabil; Zhang, Xiao-Yong; Pfeiffer, Harla K; Nissim, Ilana; Daikhin, Evgueni; Yudkoff, Marc; McMahon, Steven B; Thompson, Craig B
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.
PMCID:2596212
PMID: 19033189
ISSN: 1091-6490
CID: 2484092
Glutamine addiction: a new therapeutic target in cancer
Wise, David R; Thompson, Craig B
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.
PMCID:2917518
PMID: 20570523
ISSN: 0968-0004
CID: 2484082
Implementing and Optimizing Universal Germline Genetic Testing for Patients with Prostate Cancer in Clinical Practice Consider
Shore, Neal; Armstrong, Andrew J; Barata, Pedro; Byrne, Lindsey; Hafron, Jason; Young, Sarah; Paller, Channing; Wise, David R; Ventii, Karen; Samadi, Ali; Arangua, Paul; Werahera, Priya N; Lorentz, Justin
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.
PMID: 39909130
ISSN: 1527-9995
CID: 5784062
Implementation of Universal Germline Genetic Testing Into Standard of Care for Patients With Prostate Cancer: The Time Is Now
Shore, Neal; Nielsen, Sarah M; Esplin, Edward D; Antonarakis, Emmanuel S; Barata, Pedro C; Beer, Tomasz M; Beltran, Himisha; Bryce, Alan; Cookson, Michael S; Crawford, E David; Dorff, Tanya B; George, Daniel J; Heath, Elisabeth I; Helfand, Brian T; Hussain, Maha; Mckay, Rana R; Morgans, Alicia K; Morris, Michael J; Paller, Channing J; Ross, Ashley E; Sartor, Oliver; Shen, John; Sieber, Paul; Smith, Matthew R; Wise, David R; Armstrong, Andrew J
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.
PMID: 39700441
ISSN: 2688-1535
CID: 5764772
Clinician-Reported Management Recommendations in Response to Universal Germline Genetic Testing in Patients With Prostate Cancer
Shore, Neal; Pieczonka, Christopher; Heron, Sean; Gazi, Mukaram; Cahn, David; Belkoff, Laurence H; Berger, Aaron; Mazzarella, Brian; Veys, Joseph; Idom, Charles; Morris, David; Jayram, Gautam; Engelman, Alexander; Dato, Paul; Bevan-Thomas, Richard; Wise, David R; Hardwick, Mary Kay; Rojahn, Susan; Layman, Paige; Heald, Brandie; Ellsworth, Rachel E; Hatchell, Kathryn E; Nussbaum, Robert L; Nielsen, Sarah M; Esplin, Edward D
PURPOSE/UNASSIGNED:Identification of pathogenic germline variants in patients with prostate cancer can help inform treatment selection, screening for secondary malignancies, and cascade testing. Limited real-world data are available on clinician recommendations following germline genetic testing in patients with prostate cancer. MATERIALS AND METHODS/UNASSIGNED:< .05. Logistic regression was performed to assess the influence of test results in clinical decision-making while controlling for time of diagnosis (newly vs previously diagnosed). RESULTS/UNASSIGNED:< .001) when controlling for new or previous diagnosis. CONCLUSIONS/UNASSIGNED:Germline genetic testing results informed clinical recommendations for patients with prostate cancer, especially in patients with positive results. Higher than anticipated rates of clinical management changes in patients with uncertain results highlight the need for increased genetic education of clinicians treating patients with prostate cancer.
PMID: 39121056
ISSN: 1527-3792
CID: 5696942
High-volume prostate biopsy core involvement is not associated with an increased risk of cancer recurrence following 5-fraction stereotactic body radiation therapy monotherapy
Lischalk, Jonathan W; Sanchez, Astrid; Santos, Vianca F; Mendez, Christopher; Akerman, Meredith; Carpenter, Todd; Tam, Moses; Byun, David; Wise, David R; Mahadevan, Anand; Evans, Andrew; Huang, William; Katz, Aaron; Lepor, Herbert; Haas, Jonathan A
PURPOSE/OBJECTIVE:Percentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor. METHODS:A large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement. RESULTS:From 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234). CONCLUSIONS:With a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited.
PMCID:10913228
PMID: 38439040
ISSN: 1748-717x
CID: 5664372
TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing
Loeb, Stacy; Keith, Scott W; Cheng, Heather H; Leader, Amy E; Gross, Laura; Sanchez Nolasco, Tatiana; Byrne, Nataliya; Hartman, Rebecca; Brown, Lauren H; Pieczonka, Christopher Michael; Gomella, Leonard G; Kelly, William Kevin; Lallas, Costas D; Handley, Nathan; Mille, Patrick Johnston; Mark, James Ryan; Brown, Gordon Andrew; Chopra, Sameer; McClellan, Alexandra; Wise, David R; Hollifield, Lucas; Giri, Veda N
PURPOSE/OBJECTIVE:Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services. METHODS:Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at baseline, after pretest education/counseling, and after GT result disclosure. The primary end point was noninferiority in reducing decisional conflict between webtool and GC using the validated Decisional Conflict Scale. Mixed-effects regression modeling was used to compare decisional conflict between groups. Participants opting for GT received a 51-gene panel, with results delivered to participants and their providers. RESULTS:= .01), suggesting the patient-driven webtool was noninferior to GC. Overall, 145 (89.5%) GC and 120 (78.4%) in the webtool arm underwent GT, with pathogenic variants in 15.8% (8.7% in PCA genes). Satisfaction did not differ significantly between arms; knowledge of cancer genetics was higher but attitudes toward GT were less favorable in the webtool arm. CONCLUSION/CONCLUSIONS:The results of the TARGET study support the use of patient-driven digital webtools for expanding access to pretest genetic education for PCA GT. Further studies to optimize patient experience and evaluate them in diverse patient populations are warranted.
PMCID:10939575
PMID: 38452310
ISSN: 2473-4284
CID: 5645652
A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC)
Wise, David R; Pachynski, Russell K; Denmeade, Samuel R; Aggarwal, Rahul R; Deng, Jiehui; Febles, Victor Adorno; Balar, Arjun V; Economides, Minas P; Loomis, Cynthia; Selvaraj, Shanmugapriya; Haas, Michael; Kagey, Michael H; Newman, Walter; Baum, Jason; Troxel, Andrea B; Griglun, Sarah; Leis, Dayna; Yang, Nina; Aranchiy, Viktoriya; Machado, Sabrina; Waalkes, Erika; Gargano, Gabrielle; Soamchand, Nadia; Puranik, Amrutesh; Chattopadhyay, Pratip; Fedal, Ezeddin; Deng, Fang-Ming; Ren, Qinghu; Chiriboga, Luis; Melamed, Jonathan; Sirard, Cynthia A; Wong, Kwok-Kin
BACKGROUND:Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS:(combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS:18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION/CONCLUSIONS:DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.
PMID: 38341461
ISSN: 1476-5608
CID: 5635542
Case Series of Men with the Germline APC I1307K variant and Treatment-Emergent Neuroendocrine Prostate Cancer
Economides, Minas P; Nakazawa, Mari; Lee, Jonathan W; Li, Xiaochun; Hollifield, Lucas; Chambers, Rachelle; Sarfaty, Michal; Goldberg, Judith D; Antonarakis, Emmanuel S; Wise, David R
INTRODUCTION/BACKGROUND:Somatic mutations in the Wnt signaling gene Adenomatous Polyposis Coli (APC) promote metastatic prostate cancer (PCa) progression. Less is known regarding the impact of germline APC mutations on PCa outcomes. We sought to investigate the prevalence of aggressive variant PCa (AVPC) and treatment-emergent neuroendocrine PCa (t-NEPC) in patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men. MATERIALS AND METHODS/METHODS:We report a retrospective cohort study comparing patients with PCa and either APC I1307K germline mutation, APC somatic mutations, or unselected patients. Proportions of patients with AVPC among all the cases were estimated along with 95% Clopper-Pearson exact confidence intervals (CI). Odds ratios with 95% CI were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC. RESULTS:From 2016-2022, 18 patients with PCa at 3 institutions with the germline APC (I1307K) mutation were identified. Clinically-defined AVPC was found in 8 of the 15 cases with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). When compared to 20 patients with APC somatic frameshift mutations, patients with the germline APC I1307K variant had a significantly increased risk of AVPC (OR 7.2; 95% CI 1.27, 40.68). CONCLUSION/CONCLUSIONS:PCa that develops in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC.
PMID: 37482523
ISSN: 1938-0682
CID: 5618802